Intranasal DHE for the Treatment of Headache

ABSTRACT

Presented herein are powder formulations comprising dihydroergotamine (DHE), or a pharmaceutically acceptable salt thereof. In addition to such formulations, also presented herein are methods comprising intranasally administering powder formulations comprising dihydroergotamine, or a pharmaceutically acceptable salt thereof. The presented methods can be used for treating headache, for example, for rapid onset treatment of headache, including migraine, e.g. acute treatment of migraine with or without aura.

1. CROSS-REFERENCE

This application is a continuation of U.S. patent application Ser. No.15/023,206 filed Mar. 18, 2016, which is National Stage Entry ofPCT/IB2014/002706 filed Sep. 24, 2014, which claims the benefit of U.S.Provisional Patent Application Ser. No. 61/881,947, filed Sep. 24, 2013,each of which is entirely incorporated herein by reference.

2. BACKGROUND

Migraine is a very common, often debilitating, form of headache.Typically the headache is unilateral (affecting one half of the head)and pulsating in nature. In addition to head pain, associated symptomsmay include nausea, vomiting, photophobia, (increased sensitivity tolight), and phonophobia (increased sensitivity to sound). Migraines canalso be associated with “auras,” which are transient visual, sensory,language, or motor disturbances often manifest as flashes of colored orblinking lights that occur shortly before the onset of head pain.

Symptomatic treatment of migraine generally involves administration oftriptans, such as sumatriptan or zolmitriptan, or ergot alkaloids, suchas ergotamine or dihydroergotamine. While various routes ofadministration of these drugs for the treatment of migraine have beenutilized, there still exists a need for easily administrable,fast-acting drug formulations and treatments for the amelioration ofmigraine symptoms.

3. SUMMARY OF THE INVENTION

The inventive embodiments provided in this Summary of the Invention aremeant to be illustrative only and to provide an overview of selectiveembodiments disclosed herein. The Summary of the Invention, beingillustrative and selective, does not limit the scope of any claim, doesnot provide the entire scope of inventive embodiments disclosed orcontemplated herein, and should not be construed as limiting orconstraining the scope of this disclosure or any claimed inventiveembodiment.

The pharmacokinetic data disclosed herein (e.g., C_(max), T_(max),AUC_(0-t), AUC_(0-480 minutes), AUC_(0-inf), T_(1/2)) can be measuredfrom a primate, preferably a monkey, and preferably a Cynomolgus monkey,after a powder formulation disclosed herein is administered.Alternatively, the pharmacokinetic data disclosed herein (e.g., C_(max),T_(max), AUC_(0-t), AUC_(0-480 minutes), AUC_(0-inf), T_(1/2)) can bemeasured from a human subject after a powder formulation disclosedherein is administered.

Presented herein are powder formulations comprising dihydroergotamine(DHE), or a pharmaceutically acceptable salt thereof. In addition tosuch formulations, also presented herein are methods comprisingintranasally administering powder formulations comprisingdihydroergotamine, or a pharmaceutically acceptable salt thereof. Insome cases, the formulation is not a liquid solution or a liquid sprayformulation.

The presented methods can be used for treating headache, for example,for rapid onset treatment of headache, including migraine, e.g. acutetreatment of migraine with or without aura.

The presented formulations can comprise a) dihydroergotamine (DHE) or apharmaceutically acceptable salt thereof, wherein the total dose of DHEadministered is 0.1-10.0 mg; b) a microcrystalline cellulose comprisesat least 15% of the total weight of the formulation. In some cases, amean T_(max) of DHE after administration of the powder formulation isabout 1-120 minutes. The presented methods can comprise: intranasallyadministering to a human a powder formulation comprising: a)dihydroergotamine (DHE) or a pharmaceutically acceptable salt thereof,wherein the total dose of DHE administered is 0.1-10.0 mg; b) amicrocrystalline cellulose comprises at least 15% of the total weight ofthe formulation.

The presented formulations and methods may further comprise at least oneof the following: a) wherein a mean T_(max) of DHE after administrationof the powder formulation is about 1 to about 120 minutes; b) wherein a(AUC_(0-30 min)/AUC_(0-inf))×100% of DHE after administration of thepowder formulation is greater than 2.5%; c) wherein a(AUC_(0-30 min)/AUC_(0-inf))×100% of DHE after administration of thepowder formulation is greater than 2.5% to 25%; d) wherein a(AUC_(0-60 min)/AUC_(0-inf))×100% of DHE after administration of thepowder formulation is greater than 10%; e) wherein a(AUC_(0-60 min)/AUC_(0-inf))×100% of DHE after administration of thepowder formulation is greater than 10% to 45%; f) wherein a(AUC_(0-120 min)/AUC_(0-inf))×100% of DHE after administration of thepowder formulation is greater than 25%; g) wherein a(AUC_(0-120 min)/AUC_(0-inf))×100% of DHE after administration of thepowder formulation is greater than 25% to 75%; h) wherein when thepowder formulation is administered to a primate, preferably a monkey,and preferably a Cynomolgus monkey, a (AUC_(0-30 min)/AUC_(0-inf))×100%is greater than 10%; i) wherein when the powder formulation isadministered to a primate, preferably a monkey, and preferably aCynomolgus monkey, a (AUC_(0-60 min)/AUC₀ inf)×100% is greater than 20%;j) wherein when the powder formulation is administered to a primate,preferably a monkey, and preferably a Cynomolgus monkey, a(AUC_(0-120 min)/AUC_(0-inf))×100% is greater than 40%. The mean T_(max)after administration of the powder formulation can be measured from aprimate, preferably a monkey, and preferably a Cynomolgus monkey.

In some embodiments, a (AUC_(0-30 min)/AUC_(0-inf))×100% of DHE afteradministration of the powder formulation is greater than 2.5%, forexample, greater than 2.5%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, or30%. In some embodiments, the (AUC_(0-30 min)/AUC_(0-inf))×100% of DHEafter administration of the powder formulation is greater than 2.5% to75%, for example, 2.5% to 50%, 2.5% to 25%, 2.5% to 15%, or 2.5% to 5%.In some embodiments, a (AUC_(0-60 min)/AUC_(0-inf))×100% of DHE afteradministration of the powder formulation is greater than 5%, forexample, greater than 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%,40%, 45%, 50%, 55%, or 60%. In some embodiments, the(AUC_(0-60 min)/AUC_(0-inf))×100% of DHE after administration of thepowder formulation is greater than 5% to 75%, for example, 5% to 50%, 5%to 25%, 5% to 15%, 5% to 10%, 10% to 50%, 10% to 45%, 10% to 25%, 10% to15%, 15% to 50%, 15% to 25%, or 25% to 50%. In some embodiments, a(AUC_(0-120 min)/AUC_(0-inf))×100% of DHE after administration of thepowder formulation is greater than 5%, for example, greater than 5%, 6%,7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%,70%, or 75%. In some embodiments, the (AUC_(0-120 min)/AUC_(0-inf))×100%of DHE after administration of the powder formulation is greater than15% to 75%, for example, 15% to 75%, 15% to 50%, 15% to 25%, 25% to 75%,25% to 50%, or 50% to 75%.

In some embodiments, when the powder formulation is administered to aprimate, preferably a monkey, and preferably a Cynomolgus monkey, a(AUC_(0-30 min)/AUC_(0-inf))×100% of DHE after administration of thepowder formulation is greater than 2.5%, for example, greater than 2.5%,5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, or 30%. In some embodiments, the(AUC_(0-30 min)/AUC_(0-inf))×100% of DHE after administration of thepowder formulation is greater than 2.5% to 75%, for example, 2.5% to50%, 2.5% to 25%, 2.5% to 15%, or 2.5% to 5%. For example, the(AUC_(0-30 min)/AUC_(0-inf))×100% of DHE after administration of thepowder formulation is about 10%. In some embodiments, when the powderformulation is administered to a primate, preferably a monkey, andpreferably a Cynomolgus monkey, a (AUC_(0-60 min)/AUC_(0-inf))×100% ofDHE after administration of the powder formulation is greater than 5%,for example, greater than 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%,35%, 40%, 45%, 50%, 55%, or 60%. In some embodiments, the(AUC_(0-60 min)/AUC_(0-inf))×100% of DHE after administration of thepowder formulation is greater than 5% to 75%, for example, 5% to 50%, 5%to 25%, 5% to 15%, 5% to 10%, 10% to 50%, 10% to 45%, 10% to 25%, 10% to15%, 15% to 50%, 15% to 25%, or 25% to 50%. For example, the(AUC_(0-60 min)/AUC_(0-inf))×100% of DHE after administration of thepowder formulation is about 20%. In some embodiments, when the powderformulation is administered to a primate, preferably a monkey, andpreferably a Cynomolgus monkey, a (AUC_(0-120 min)/AUC_(0-inf))×100% ofDHE after administration of the powder formulation is greater than 5%,for example, greater than 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%,35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, or 75%. In some embodiments, the(AUC_(0-120 min)/AUC_(0-inf))×100% of DHE after administration of thepowder formulation is greater than 15% to 75%, for example, 15% to 75%,15% to 50%, 15% to 25%, 25% to 75%, 25% to 50%, or 50% to 75%. Forexample, the (AUC_(0-120 min)/AUC_(0-inf))×100% of DHE afteradministration of the powder formulation is about 40%.

The presented formulations can comprise a) dihydroergotamine (DHE) or apharmaceutically acceptable salt thereof, wherein the total dose of DHEadministered is 0.1-10.0 mg; b) a microcrystalline cellulose comprisesat least 15% of the total weight of the formulation. In some cases, amean T_(max) of DHE after administration of the powder formulation isabout 1-120 minutes. The presented methods can comprise: intranasallyadministering to a human a powder formulation comprising: a)dihydroergotamine (DHE) or a pharmaceutically acceptable salt thereof,wherein the total dose of DHE administered is 0.1-10.0 mg; b) amicrocrystalline cellulose comprises at least 15% of the total weight ofthe formulation; wherein a mean T_(max) of DHE after administration ofthe powder formulation is about 1-120 minutes. The mean T_(max) afteradministration of the powder formulation can be measured from a humansubject.

In one embodiment, the methods and formulations comprise a mean T_(max)of DHE after administration of the formulation of at least about 1minutes, for example, at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11,12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 60, 90, or120 minutes. The mean T_(max) of DHE after administration of theformulation can be about 1 to about 120 minutes, for example, about1-120 minutes, about 1-90 minutes, about 1-60 minutes, about 1-50minutes, 1-40 minutes, 1-30 minutes, 1-20 minutes, 1-10 minutes, 1-5minutes, about 1-2 minutes, about 5-120 minutes, about 5-90 minutes,about 5-60 minutes, about 5-50 minutes, 5-40 minutes, 5-30 minutes, 5-25minutes, 5-20 minutes, 5-10 minutes, about 10-120 minutes, about 10-90minutes, about 10-60 minutes, about 10-50 minutes, 10-40 minutes, 10-30minutes, 10-20 minutes, about 20-120 minutes, about 20-90 minutes, about20-60 minutes, about 20-50 minutes, 20-40 minutes, 20-30 minutes, about30-120 minutes, about 30-90 minutes, about 30-60 minutes, about 30-50minutes, 30-40 minutes, about 40-120 minutes, about 40-90 minutes, about40-60 minutes, 40-50 minutes, about 50-120 minutes, about 50-90 minutes,about 50-60 minutes, about 60-120 minutes, about 60-90 minutes, or about90-120 minutes. The mean T_(max) after administration of the powderformulation can be measured from a primate, preferably a monkey, andpreferably a Cynomolgus monkey.

In another embodiment, the methods and formulations comprise a meanT_(max) of DHE after administration of the formulation of at least about1 minute, for example, at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11,12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 60, 90, or120 minutes. The mean T_(max) of DHE after administration of theformulation can be about 1 to about 120 minutes, for example, about1-120 minutes, about 1-90 minutes, about 1-60 minutes, about 1-50minutes, 1-40 minutes, 1-30 minutes, 1-20 minutes, 1-10 minutes, 1-5minutes, about 1-2 minutes, about 5-120 minutes, about 5-90 minutes,about 5-60 minutes, about 5-50 minutes, 5-40 minutes, 5-30 minutes, 5-25minutes, 5-20 minutes, 5-10 minutes, about 10-120 minutes, about 10-90minutes, about 10-60 minutes, about 10-50 minutes, 10-40 minutes, 10-30minutes, 10-20 minutes, about 20-120 minutes, about 20-90 minutes, about20-60 minutes, about 20-50 minutes, 20-40 minutes, 20-30 minutes, about30-120 minutes, about 30-90 minutes, about 30-60 minutes, about 30-50minutes, 30-40 minutes, about 40-120 minutes, about 40-90 minutes, about40-60 minutes, 40-50 minutes, about 50-120 minutes, about 50-90 minutes,about 50-60 minutes, about 60-120 minutes, about 60-90 minutes, or about90-120 minutes. The mean T_(max) after administration of the powderformulation can be measured from a human subject.

In another embodiment, the methods and formulations comprise a meanC_(max) of DHE after administration of the formulation of at least about0.01 ng/mL, for example, at least about 0.01, 0.1, 0.2, 0.3, 0.4, 0.5,0.6, 0.7, 0.8, 0.9, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7,7.5, 8, 8.5, 9, 9.5, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30,35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130,140, or 150 ng/mL. The mean C_(max) of DHE after administration of theformulation can be about 0.1 to about 150 ng/mL, for example, about0.1-150, 0.1-130, 0.1-110, 0.1-90, 0.1-70, 0.1-50, 0.1-30, 0.1-10,0.1-5, 0.1-1.0, 0.1-0.5, 1-150, 1-130, 1-110, 1-90, 1-70, 1-50, 1-30,1-10, 1-5, 5-150, 5-130, 5-110, 5-90, 5-70, 5-50, 5-30, 5-10, 10-150,10-130, 10-110, 10-90, 10-70, 10-50, 10-30, 30-150, 30-130, 30-110,30-90, 30-70, 30-50, 50-150, 50-130, 50-110, 50-90, 50-70, 70-150,70-130, 70-110, 70-90, 90-150, 90-130, 90-110, 110-150, 110-130, or130-150 ng/mL. The mean C_(max) after administration of the powderformulation can be measured from a primate, preferably a monkey, andpreferably a Cynomolgus monkey.

In another embodiment, the methods and formulations comprise a meanC_(max) of DHE after administration of the formulation of at least about0.01 ng/mL, for example, at least about 0.01, 0.1, 0.2, 0.3, 0.4, 0.5,0.6, 0.7, 0.8, 0.9, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7,7.5, 8, 8.5, 9, 9.5, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30,35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130,140, or 150 ng/mL. The mean C_(max) of DHE after administration of theformulation can be about 0.1 to about 150 ng/mL, for example, about0.1-150, 0.1-130, 0.1-110, 0.1-90, 0.1-70, 0.1-50, 0.1-30, 0.1-10,0.1-5, 0.1-1.0, 0.1-0.5, 1-150, 1-130, 1-110, 1-90, 1-70, 1-50, 1-30,1-10, 1-5, 5-150, 5-130, 5-110, 5-90, 5-70, 5-50, 5-30, 5-10, 10-150,10-130, 10-110, 10-90, 10-70, 10-50, 10-30, 30-150, 30-130, 30-110,30-90, 30-70, 30-50, 50-150, 50-130, 50-110, 50-90, 50-70, 70-150,70-130, 70-110, 70-90, 90-150, 90-130, 90-110, 110-150, 110-130, or130-150 ng/mL. The mean C_(max) after administration of the powderformulation can be measured from a human subject.

In another embodiment, the methods and formulations comprise a meanAUC_(0-inf) of DHE after administration of the formulation of at leastabout 0.5 ng·h/mL, for example, at least about 0.5, 1, 2, 3, 4, 5, 6, 7,8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400, 500, 600,or 700 ng·h/mL. The mean AUC_(0-inf) of DHE after administration of theformulation can be about 0.5 to about 700 ng·h/mL, for example, about0.5-700, 0.5-500, 0.5-300, 0.5-100, 0.5-80, 0.5-60, 0.5-40, 0.5-20,0.5-10, 0.5-5, 0.5-2, 0.5-1, 1-700, 1-500, 1-300, 1-100, 1-80, 1-60,1-40, 1-20, 1-10, 1-5, 10-700, 10-500, 10-300, 10-100, 10-80, 10-60,10-40, 10-20, 20-700, 20-500, 20-300, 20-100, 20-80, 20-60, 20-40,40-700, 40-500, 40-300, 40-100, 40-80, 40-60, 60-700, 60-500, 60-300,60-100, 60-80, 80-700, 80-500, 80-300, 80-100, 100-700, 100-500,100-300, 300-700, 300-500, or 500-700 ng·h/mL. The mean AUC_(0-inf)after administration of the powder formulation can be measured fr from aprimate, preferably a monkey, and preferably a Cynomolgus monkey.

In another embodiment, the methods and formulations comprise a meanAUC_(0-inf) of DHE after administration of the formulation of at leastabout 0.5 ng·h/mL, for example, at least about 0.5, 1, 2, 3, 4, 5, 6, 7,8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400, 500, 600,or 700 ng·h/mL. The mean AUC_(0-inf) of DHE after administration of theformulation can be about 0.5 to about 700 ng·h/mL, for example, about0.5-700, 0.5-500, 0.5-300, 0.5-100, 0.5-80, 0.5-60, 0.5-40, 0.5-20,0.5-10, 0.5-5, 0.5-2, 0.5-1, 1-700, 1-500, 1-300, 1-100, 1-80, 1-60,1-40, 1-20, 1-10, 1-5, 10-700, 10-500, 10-300, 10-100, 10-80, 10-60,10-40, 10-20, 20-700, 20-500, 20-300, 20-100, 20-80, 20-60, 20-40,40-700, 40-500, 40-300, 40-100, 40-80, 40-60, 60-700, 60-500, 60-300,60-100, 60-80, 80-700, 80-500, 80-300, 80-100, 100-700, 100-500,100-300, 300-700, 300-500, or 500-700 ng·h/mL. The mean AUC_(0-inf)after administration of the powder formulation can be measured from ahuman subject.

In another embodiment, the methods and formulations comprise a meanAUC_(0-t) of DHE after administration of the formulation of at leastabout 0.5 ng·h/mL, for example, at least about 0.5, 1, 2, 3, 4, 5, 6, 7,8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400, 500, 600,or 700 ng·h/mL. The mean AUC_(0-inf) of DHE after administration of theformulation can be about 0.5 to about 700 ng·h/mL, for example, about0.5-700, 0.5-500, 0.5-300, 0.5-100, 0.5-80, 0.5-60, 0.5-40, 0.5-20,0.5-10, 0.5-5, 0.5-2, 0.5-1, 1-700, 1-500, 1-300, 1-100, 1-80, 1-60,1-40, 1-20, 1-10, 1-5, 10-700, 10-500, 10-300, 10-100, 10-80, 10-60,10-40, 10-20, 20-700, 20-500, 20-300, 20-100, 20-80, 20-60, 20-40,40-700, 40-500, 40-300, 40-100, 40-80, 40-60, 60-700, 60-500, 60-300,60-100, 60-80, 80-700, 80-500, 80-300, 80-100, 100-700, 100-500,100-300, 300-700, 300-500, or 500-700 ng·h/mL. The mean AUC_(0-inf)after administration of the powder formulation can be measured from aprimate, preferably a monkey, and preferably a Cynomolgus monkey. Themeasurement can be taken 5, 10, 20, 30, 60, 90, 120, 180, 240, 300, 360,420, or 480 minutes.

In another embodiment, the methods and formulations comprise a meanAUC_(0-t) of DHE after administration of the formulation of at leastabout 0.5 ng·h/mL, for example, at least about 0.5, 1, 2, 3, 4, 5, 6, 7,8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400, 500, 600,or 700 ng·h/mL. The mean AUC_(0-inf) of DHE after administration of theformulation can be about 0.5 to about 700 ng·h/mL, for example, about0.5-700, 0.5-500, 0.5-300, 0.5-100, 0.5-80, 0.5-60, 0.5-40, 0.5-20,0.5-10, 0.5-5, 0.5-2, 0.5-1, 1-700, 1-500, 1-300, 1-100, 1-80, 1-60,1-40, 1-20, 1-10, 1-5, 10-700, 10-500, 10-300, 10-100, 10-80, 10-60,10-40, 10-20, 20-700, 20-500, 20-300, 20-100, 20-80, 20-60, 20-40,40-700, 40-500, 40-300, 40-100, 40-80, 40-60, 60-700, 60-500, 60-300,60-100, 60-80, 80-700, 80-500, 80-300, 80-100, 100-700, 100-500,100-300, 300-700, 300-500, or 500-700 ng·h/mL. The mean AUC_(0-inf)after administration of the powder formulation can be measured from ahuman subject. The measurement can be taken 5, 10, 20, 30, 60, 90, 120,180, 240, 300, 360, 420, or 480 minutes.

In another embodiment, the methods and formulations comprise a meanT_(1/2) of DHE after administration of the formulation of at least about10 minutes, for example, at least about 10, 20, 30, 40, 50, 60, 70, 80,90, 100, 120, 150, 200, 250, or 300 minutes. The mean T_(1/2) of DHEafter administration of the formulation can be about 10 to about 300minutes, for example, about 10-300, 10-250, 10-200, 10-150, 10-120,10-100, 10-80, 10-60, 10-40, 10-20, 20-300, 20-250, 20-200, 20-150,20-120, 20-100, 20-80, 20-60, 20-40, 40-300, 40-250, 40-200, 40-150,40-120, 40-100, 40-80, 40-60, 60-300, 60-250, 60-200, 60-150, 60-120,60-100, 60-80, 80-300, 80-250, 80-200, 80-150, 80-120, 80-100, 100-300,100-250, 100-200, 100-150, 100-120, 120-300, 120-250, 120-200, 120-150,150-300, 150-250, 150-200, 200-300, 200-250, or 250-300 minutes. Forexample, the mean T_(1/2) of DHE after administration of the formulationis about 100 to about 300 minutes. The mean T_(1/2) after administrationof the powder formulation can be measured from a monkey (e.g.,Cynomolgus monkeys).

In another embodiment, the methods and formulations comprise a meanT_(1/2) of DHE after administration of the formulation of at least about10 minutes, for example, at least about 10, 20, 30, 40, 50, 60, 70, 80,90, 100, 120, 150, 200, 250, or 300 minutes. The mean T_(1/2) of DHEafter administration of the formulation can be about 10 to about 300minutes, for example, about 10-300, 10-250, 10-200, 10-150, 10-120,10-100, 10-80, 10-60, 10-40, 10-20, 20-300, 20-250, 20-200, 20-150,20-120, 20-100, 20-80, 20-60, 20-40, 40-300, 40-250, 40-200, 40-150,40-120, 40-100, 40-80, 40-60, 60-300, 60-250, 60-200, 60-150, 60-120,60-100, 60-80, 80-300, 80-250, 80-200, 80-150, 80-120, 80-100, 100-300,100-250, 100-200, 100-150, 100-120, 120-300, 120-250, 120-200, 120-150,150-300, 150-250, 150-200, 200-300, 200-250, or 250-300 minutes. Forexample, the mean T_(1/2) of DHE after administration of the formulationis about 100 to about 300 minutes. The mean T_(1/2) after administrationof the powder formulation can be measured from a human subject.

In another aspect, the methods presented herein comprising intranasallyadministering to a human a powder formulation comprisingdihydroergotamine (DHE) or a pharmaceutically acceptable salt thereof.wherein the method further comprises at least one of the following:wherein a mean T_(max) of DHE after administration of the formulation isabout 2 to about 50 minutes; b) wherein a mean C_(max) of DHE afteradministration of the formulation is about 0.1 to about 150 ng/mL; c)wherein a mean AUC_(0-inf) of DHE after administration of theformulation is about 1 to about 700 ng·h/mL; d) wherein a mean T_(1/2)of DHE after administration of the formulation is about 100 to about 300minutes. In one embodiment, the mean T_(max) of DHE after administrationof the formulation is about 2 to about 50 minutes. In anotherembodiment, the mean C_(max) of DHE after administration of theformulation is about 0.1 to about 150 ng/mL. In another embodiment, themean AUC_(0-inf) of DHE after administration of the formulation is about1 to about 700 ng·h/mL. In another embodiment, the mean T_(1/2) of DHEafter administration of the formulation is about 100 to about 300minutes. The mean T_(max), C_(max), AUC_(0-inf), and/or T_(1/2) afteradministration of the powder formulation can be measured from a primate,preferably a monkey, and preferably a Cynomolgus monkey.

In another aspect, the methods presented herein comprising intranasallyadministering to a human a powder formulation comprisingdihydroergotamine (DHE) or a pharmaceutically acceptable salt thereof.wherein the method further comprises at least one of the following:wherein a mean T_(max) of DHE after administration of the formulation isabout 2 to about 50 minutes; b) wherein a mean C_(max) of DHE afteradministration of the formulation is about 0.1 to about 150 ng/mL; c)wherein a mean AUC_(0-inf) of DHE after administration of theformulation is about 1 to about 700 ng·h/mL; d) wherein a mean T_(1/2)of DHE after administration of the formulation is about 100 to about 300minutes. In one embodiment, the mean T_(max) of DHE after administrationof the formulation is about 2 to about 50 minutes. In anotherembodiment, the mean C_(max) of DHE after administration of theformulation is about 0.1 to about 150 ng/mL. In another embodiment, themean AUC_(0-inf) of DHE after administration of the formulation is about1 to about 700 ng·h/mL. In another embodiment, the mean T_(1/2) of DHEafter administration of the formulation is about 100 to about 300minutes. The mean T_(max), C_(max), AUC_(0-inf), and/or T_(1/2) afteradministration of the powder formulation can be measured from a humansubject.

In one case, the mean T_(max) of DHE is about 10 to about 30 minutes,the mean C_(max) of DHE is about 0.5 to about 6 ng/mL, the meanAUC_(0-inf) of DHE is about 1 to about 15 ng·h/mL, and the mean T_(1/2)of DHE is about 100 to about 300 minutes. In another case, the meanT_(max) of DHE is about 10 to about 50 minutes, the mean C_(max) of DHEis about 1 to about 15 ng/mL, the mean AUC_(0-inf) of DHE is about 10 toabout 50 ng·h/mL, and the mean T_(1/2) of DHE is about 100 to about 300minutes. In another case, the mean T_(max) of DHE is about 10 to about50 minutes, the mean C_(max) of DHE is about 2 to about 20 ng/mL, themean AUC_(0-inf) of DHE is about 15 to about 110 ng·h/mL, and the meanT_(1/2) of DHE is about 100 to about 300 minutes. In another case, themean T_(max) of DHE is about 10 to about 50 minutes, the mean C_(max) ofDHE is about 2 to about 50 ng/mL, the mean AUC_(0-inf) of DHE is about15 to about 200 ng·h/mL, and the mean T_(1/2) of DHE is about 100 toabout 300 minutes. The mean T_(max), C_(max), AUC_(0-inf), and/orT_(1/2) after administration of the powder formulation can be measuredfrom a primate, preferably a monkey, and preferably a Cynomolgus monkey.

In one case, the mean T_(max) of DHE is about 10 to about 30 minutes,the mean C_(max) of DHE is about 0.5 to about 6 ng/mL, the meanAUC_(0-inf) of DHE is about 1 to about 15 ng·h/mL, and the mean T_(1/2)of DHE is about 100 to about 300 minutes. In another case, the meanT_(max) of DHE is about 10 to about 50 minutes, the mean C_(max) of DHEis about 1 to about 15 ng/mL, the mean AUC_(0-inf) of DHE is about 10 toabout 50 ng·h/mL, and the mean T_(1/2) of DHE is about 100 to about 300minutes. In another case, the mean T_(max) of DHE is about 10 to about50 minutes, the mean C_(max) of DHE is about 2 to about 20 ng/mL, themean AUC_(0-inf) of DHE is about 15 to about 110 ng·h/mL, and the meanT_(1/2) of DHE is about 100 to about 300 minutes. In another case, themean T_(max) of DHE is about 10 to about 50 minutes, the mean C_(max) ofDHE is about 2 to about 50 ng/mL, the mean AUC_(0-inf) of DHE is about15 to about 200 ng·h/mL, and the mean T_(1/2) of DHE is about 100 toabout 300 minutes. The mean T_(max), C_(max), AUC_(0-inf), and/orT_(1/2) after administration of the powder formulation can be measuredfrom a human subject.

In some cases, the powder formulation is administered such that theintersubject variability in DHE C_(max) is less than 30%. For example,the intersubject variability in DHE C_(max) is less than 30%, 25%, 20%,15%, 10%, or 5%. In some cases, the powder formulation is administeredsuch that the intersubject variability in DHE T_(max) is less than 30%.For example, the intersubject variability in DHE T_(max) is less than30%, 25%, 20%, 15%, 10%, or 5%. In some cases, the powder formulation isadministered such that the intersubject variability in DHE AUC_(0-inf)is less than 30%. For example, the intersubject variability in DHEAUC_(0-inf) is less than 30%, 25%, 20%, 15%, 10%, or 5%. In some cases,the powder formulation is administered such that the intersubjectvariability in DHE T_(1/2) is less than 30%. For example, theintersubject variability in DHE T_(1/2) is less than 30%, 25%, 20%, 15%,10%, or 5%. The intersubject variability in DHE T_(max), C_(max),AUC_(0-inf), and/or T_(1/2) after administration of the powderformulation can be measured from primates, preferably monkeys, andpreferably a Cynomolgus monkeys.

In some cases, the powder formulation is administered such that theintersubject variability in DHE C_(max) is less than 30%. For example,the intersubject variability in DHE C_(max) is less than 30%, 25%, 20%,15%, 10%, or 5%. In some cases, the powder formulation is administeredsuch that the intersubject variability in DHE T_(max) is less than 30%.For example, the intersubject variability in DHE T_(max) is less than30%, 25%, 20%, 15%, 10%, or 5%. In some cases, the powder formulation isadministered such that the intersubject variability in DHE AUC_(0-inf)is less than 30%. For example, the intersubject variability in DHEAUC_(0-inf) is less than 30%, 25%, 20%, 15%, 10%, or 5%. In some cases,the powder formulation is administered such that the intersubjectvariability in DHE T_(1/2) is less than 30%. For example, theintersubject variability in DHE T_(1/2) is less than 30%, 25%, 20%, 15%,10%, or 5%. The intersubject variability in DHE T_(max), C_(max),AUC_(0-inf), and/or T_(1/2) after administration of the powderformulation can be measured from human subjects.

In another embodiment, the powder formulation comprises DHE mesylate.For example, the powder formulation comprises DHE mesylate,microcrystalline cellulose, and tribasic calcium phosphate.

The methods and formulations may further comprise a microcrystallinecellulose component with a mean particle size diameter of about 100 μmor less. The microcrystalline cellulose component may have a meanparticle size diameter of less than about 100 μm, for example, about 95,90, 85, 80, 75, 70, 65, 60, 55, 50, 45, 40, 35, 30, 25, 20, 15, 10, 5 μmor less.

The microcrystalline cellulose component may comprise a firstmicrocrystalline cellulose portion with a mean particle diameter size ofabout 30 μm or less, and a second microcrystalline cellulose portionwith a mean particle size diameter of about 30 to about 100 m. The firstmicrocrystalline cellulose portion may have a mean particle diametersize of about m or less, for example, 30-25, 30-20, 30-15, 30-10, 30-5,25-20, 25-15, 25-10, 25-5, 20-15, 20-10, 20-5, 15-10, 15-5 or 10-5 μm.In a specific embodiment, the first microcrystalline cellulose portionhas a mean particle diameter size of about 15-30 μm. In another specificembodiment, the first microcrystalline cellulose portion has a meanparticle diameter size of about 18-20 μm. In yet another specificembodiment, the first microcrystalline cellulose portion has a meanparticle diameter size of about 20 μm. The second microcrystallinecellulose portion may have a mean particle diameter size of about 30 toabout 100 μm, for example, 30-90, 30-80, 30-70, 30-60, 30-50, 30-40,40-90, 40-80, 40-70, 40-60, 40-50, 50-90, 50-80, 50-70, 50-60, 60-90,60-80, 60-70, 70-90, 70-80, or 80-90 μm. In a specific embodiment, thesecond microcrystalline cellulose portion has a mean particle diametersize of about 45-65 μm. In another specific embodiment, the secondmicrocrystalline cellulose portion has a mean particle diameter size ofabout 45-55 μm. In another specific embodiment, the secondmicrocrystalline cellulose portion has a mean particle diameter size ofabout 50-55 μm. In yet another specific embodiment, the secondmicrocrystalline cellulose portion has a mean particle diameter size ofabout 50 μm.

In one embodiment, the first microcrystalline cellulose portion has amean particle diameter size of about 15 to about 30 μm and the secondmicrocrystalline cellulose portion has a mean particle diameter size ofabout 45 to about 65 μm. In another embodiment, the firstmicrocrystalline cellulose portion has a mean particle size of about 20μm and the second microcrystalline cellulose portion has a mean particlesize diameter of about 50 to about 55 μm. In yet another embodiment, thefirst microcrystalline cellulose portion has a mean particle diametersize of about 20 μm, and the second microcrystalline cellulose portionhas a mean particle size diameter of about 50 μm. In some cases, themicrocrystalline cellulose component is substantially free of particleswith a mean particle diameter size of about 31 to about 44 μm. Themethod of claim 4, wherein the microcrystalline cellulose component issubstantially free of particles with a mean particle diameter size ofabout 31 to about 49 μm. In some cases, substantially free of particleswith a mean particle diameter size means less than 15%, 10%, 5%, or 2%of all the particles fall into the given range.

In another aspect, the microcrystalline cellulose component may compriseat least about 5% of the total weight of the powder formulation, forexample, at least about 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%,35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 95%of the total weight of the powder formulation. The microcrystallinecellulose component may comprise about 15% to about 99% of the totalweight of the powder formulation, for example, about 15%-99%, 20%-99%,30%-99%, 40-99%, 50-99%, 60-99%, 70-99%, 80-99%, 90-99%, 15%-90%,20%-90%, 30%-90%, 40-90%, 50-90%, 60-90%, 70-90%, 80-90%, 15%-80%,20%-80%, 30%-80%, 40-80%, 50-80%, 60-80%, 70-80%, 15%-70%, 20%-70%,30%-70%, 40-70%, 50-70%, 60-70%, 15%-60%, 20%-60%, 30%-60%, 40-60%,50-60%, 15%-50%, 20%-50%, 30%-50%, 40-50%, 15%-40%, 20%-40%, 30%-40%,15%-30%, 20%-30%, or 15-20% of the total weight of the powderformulation.

In one embodiment, the first microcrystalline cellulose componentcomprises about 10 to about 90% of the total weight of the powderformulation, for example, about 10%-90%, 15%-90%, 20%-90%, 30%-90%,40-90%, 50-90%, 60-90%, 70-90%, 80-90%, 10%-80%, 15%-80%, 20%-80%,30%-80%, 40-80%, 50-80%, 60-80%, 70-80%, 10%-70%, 15%-70%, 20%-70%,30%-70%, 40-70%, 50-70%, 60-70%, 10%-60%, 15%-60%, 20%-60%, 30%-60%,40-60%, 50-60%, 10%-50%, 15%-50%, 20%-50%, 30%-50%, 40-50%, 10%-40%,15%-40%, 20%-40%, 30%-40%, 10%-30%, 15%-30%, 20%-30%, 10%-20%, 15-20%,or 10%-15% of the total weight of the powder formulation. In oneembodiment, the first microcrystalline cellulose component comprisesabout 70% to about 90% of the total weight of the powder formulation. Inanother embodiment, the first microcrystalline cellulose componentcomprises about 70% to about 90% of the total weight of the powderformulation.

In one embodiment, the second microcrystalline cellulose componentcomprises about 5% to about 15% of the total weight of the powderformulation, for example, about 5%-15%, 5%-10%, or 10%-15% of the totalweight of the powder formulation. In one embodiment, the secondmicrocrystalline cellulose component comprises about 10% of the totalweight of the powder formulation. For example, in particularembodiments, the first microcrystalline cellulose portion comprisesabout 8% to about 90% of the total weight of the formulation, and thesecond microcrystalline cellulose portion comprises about 10% of thetotal weight of the formulation. In another certain embodiment, thefirst microcrystalline cellulose portion is about 5% to about 90% of thetotal weight of the powder formulation, and the second microcrystallineportion is about 10% of the total weight of the powder formulation.

In another aspect, the methods and formulations may further comprise afluidizing agent. For example, the fluidizing agent is tribasic calciumphosphate. The tribasic calcium phosphate can be about 0.1% to about5.0% of the total weight of the powder formulation, for example about0.1%-5%, 0.1%-4%, 0.1%-3%, 0.1%-2%, 0.1%-1%, 0.1%-0.5%, 0.5%-5%,0.5%-4%, 0.5%-3%, 0.5%-2%, 0.5%-1%, 1%-5%, 1%-4%, 1%-3%, 1%-2%, 2%-5%,2%-4%, 2%-3%, 3%-5%, 3%-4%, or 4%-5% of the total weight of the powderformulation. In one embodiment, the tribasic calcium phosphate is about0.5% to about 1.0% of the total weight of the powder formulation. Inanother embodiment, the tribasic calcium phosphate is about 0.5% toabout 1.5% of the total weight of the powder formulation. In anotherembodiment, the tribasic calcium phosphate is about 0.8% of the totalweight of the powder formulation.

In another aspect, the methods and formulations may further comprise atleast one of the following: an adenosine receptor antagonist, aphosphodiesterase inhibitor, an acetylcholinesterase inhibitor, avasodilator, xanthine, caffeine, paraxanthine, theobromine, andtheophylline. For example, the methods and formulations further comprisecaffeine. The caffeine can be at least about 1% of the total weight ofthe powder formulation, for example about 1%, 2%, 3%, 4%, 5%, 6%, 7%,8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60% or more ofthe total weight of the powder formulation. The caffeine can be about 1%to 60% of the total weight of the powder formulation, for example, about1%-60%, 1%-50%, 1%-40%, 1%-30%, 1%-20%, 1%-10%, 1%-5%, 10%-60%, 10%-50%,10%-40%, 10%-30%, 10%-20%, 20%-60%, 20%-50%, 20%-40%, 20%-30%, 30%-60%,30%-50%, 30%-40%, 40%-60%, 40%-50%, or 50%-60% of the total weight ofthe powder formulation. In another embodiment, the powder formulationcomprises about 5% to 10% caffeine. In a particular embodiment, thecaffeine is anhydrous caffeine. In another embodiment, the powderformulation comprises about 10% to 15% caffeine.

In another aspect, a total dose of the powder formulation administeredcan be at least about 0.1 mg, for example, at least about 0.1, 0.2, 0.3,0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6,6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20,or 25 mg. The total dose of the powder formulation administered can beabout 0.1 to about 25 mg, for example, about 0.1-25.0 mg, about 0.1-20.0mg, about 0.1-15.0 mg, about 0.1-10.0 mg, about 0.1-5.0 mg, about0.1-2.0 mg, about 0.1-1.0 mg, about 0.1-0.5 mg, about 0.2-25.0 mg, about0.2-20.0 mg, about 0.2-15.0 mg, about 0.2-10.0 mg, about 0.2-5.0 mg,about 0.2-2.0 mg, about 0.2-1.0 mg, about 0.2-0.5 mg, about 0.5-25.0 mg,about 0.5-20.0 mg, about 0.5-15.0 mg, about 0.5-10.0 mg, about 0.5-5.0mg, about 0.5-2.0 mg, about 0.5-1.0 mg, about 1.0-25.0 mg, about1.0-20.0 mg, about 1.0-15.0 mg, about 1.0-10.0 mg, about 1.0-5.0 mg,about 1.0-2.0 mg, about 2.0-25.0 mg, about 2.0-20.0 mg, about 2.0-15.0mg, about 2.0-10.0 mg, about 2.0-5.0 mg, about 5.0-25.0 mg, about5.0-20.0 mg, about 5.0-15.0 mg, about 5.0-10.0 mg, about 10.0-25.0 mg,about 10.0-20.0 mg, about 10.0-15.0 mg, about 15.0-25.0 mg, or about15.0-20.0 mg. For example, the total dose of the powder formulationadministered is about 25 mg.

In another aspect, the powder formulation comprises a total dose of DHEadministered of at least about 0.1 mg, for example, at least about 0.1,0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5,5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, or 10 mg. The powder formulationmay comprise a total dose of DHE administered of about 0.1 to about 10.0mg, for example, about 0.1-10.0 mg, about 0.1-9.0 mg DHE, about 0.1-8.0mg DHE, about 0.1-7.0 mg DHE, about 0.1-6.0 mg DHE, about 0.1-5.0 mg,about 0.1-4.0 mg DHE, about 0.1-3.0 mg DHE, about 0.1-2.0 mg, about0.1-1.0 mg, about 0.1-0.5 mg, about 0.2-10.0 mg, about 0.2-9.0 mg DHE,about 0.2-8.0 mg DHE, about 0.2-7.0 mg DHE, about 0.2-6.0 mg DHE, about0.2-5.0 mg, about 0.2-4.0 mg DHE, about 0.2-3.0 mg DHE, about 0.2-2.0mg, about 0.2-1.0 mg, about 0.2-0.5 mg, about 0.5-10.0 mg, about 0.5-9.0mg DHE, about 0.5-8.0 mg DHE, about 0.5-7.0 mg DHE, about 0.5-6.0 mgDHE, about 0.5-5.0 mg, about 0.5-4.0 mg DHE, about 0.5-3.0 mg DHE, about0.5-2.0 mg, about 0.5-1.0 mg, about 1.0-10.0 mg, about 1.0-5.0 mg, about1.0-4.0 mg DHE, about 1.0-3.0 mg DHE, about 1.0-2.0 mg, about 2.0-10.0mg, about 2.0-9.0 mg DHE, about 2.0-8.0 mg DHE, about 2.0-7.0 mg DHE,about 2.0-6.0 mg DHE, about 2.0-5.0 mg, about 2.0-4.0 mg DHE, about2.0-3.0 mg DHE, about 5.0-10.0 mg, about 5.0-9.0 mg DHE, about 5.0-8.0mg DHE, about 5.0-7.0 mg DHE, about 5.0-6.0 mg DHE, about 6.0-10.0 mg,about 6.0-9.0 mg DHE, about 6.0-8.0 mg DHE, about 6.0-7.0 mg DHE, about7.0-10.0 mg, about 7.0-9.0 mg DHE, about 7.0-8.0 mg DHE, about 8.0-10.0mg, about 8.0-9.0 mg DHE, or about 9.0-10.0 mg DHE. For example, thetotal dose of DHE administered of about 0.5 mg. In certain embodiments,the total dose of DHE administered is 0.1-5.0 mg. In certain otherembodiments, the total amount of DHE administered is 0.5-5.0 mg. Incertain other embodiments, the total amount of DHE administered is0.5-3.0 mg. In certain other embodiments, the total amount of DHEadministered is 1.0-2.0 mg.

In some embodiments, the powder formulation has an angle of repose about53° or less, for example, about 53°, 52°, 51°, 50°, 48°, 46°, 44°, 42°,40°, 38°, 36°, 34°, 32°, 30°, 28°, 26°, 24°, 22°, 20° or less.

Presented herein are methods and formulations used for treatingheadache. For example, the methods and formulations are used fortreating migraine. In some cases, the methods of treating migraine aremethods for the acute treatment of migraine headaches with or withoutaura.

In one embodiment, at least a portion of the powder formulation isadministered to a single nostril of the human. In another embodiment, atleast a portion of the powder formulation is administered to eachnostril of the human. For example, in a specific embodiment of themethod, about half of the formulation is administered to one nostril andabout half of the formulation is administered to the other nostril ofthe human.

4. BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 presents pharmacokinetic profiles of DHE intranasal powderformulations, including comparisons with Migranal nasal spray, inmonkey.

FIG. 2 presents pharmacokinetic profiles of DHE intranasal powderformulations, including comparisons with Migranal nasal spray, in monkeyfrom 0 to 3 hours.

FIG. 3 presents a comparison of DHE intranasal powder formulations andMigranal nasal spray AUC from 0-30 minutes.

FIG. 4 presents pharmacokinetic profiles of caffeine vs. non-caffeinecontaining DHE intranasal powder formulations (0.5 mg DHE dose).

FIG. 5 presents pharmacokinetic profiles of 1 mg DHE powder formulationadministered to a single nostril vs. 1 mg DHE powder formulationadministered to both nostrils (“double nostril”; 0.5 mg DHEdose/nostril).

FIG. 6 presents plasma DHE concentrations in monkeys over 480 minutesafter the tested administrations.

5. DETAILED DESCRIPTION

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of the ordinaryskill in the art to which this invention belongs. Although any methodsand materials similar or equivalent to those described herein can beused in the practice or testing of the formulations or unit dosesherein, some methods and materials are now described. Unless mentionedotherwise, the techniques employed or contemplated herein are standardmethodologies. The materials, methods and examples are illustrative onlyand not limiting.

The details of one or more inventive embodiments are set forth in theaccompanying drawings, the claims, and the description herein. Otherfeatures, objects, and advantages of the inventive embodiments disclosedand contemplated herein can be combined with any other embodiment unlessexplicitly excluded.

Unless otherwise indicated, open terms for example “contain,”“containing,” “include,” “including,” and the like mean comprising.

The singular forms “a”, “an”, and “the” are used herein to includeplural references unless the context clearly dictates otherwise.Accordingly, unless the contrary is indicated, the numerical parametersset forth in this application are approximations that may vary dependingupon the desired properties sought to be obtained by the presentinvention.

Unless otherwise indicated, some embodiments herein contemplatenumerical ranges. When a numerical range is provided, unless otherwiseindicated, the range includes the range endpoints. Unless otherwiseindicated, numerical ranges include all values and subranges therein asif explicitly written out. Unless otherwise indicated, any numericalranges and/or values herein can be at 80-125% of the numerical rangesand/or values.

Unless otherwise indicated, “mean particle diameter” can refer to theparticle size distribution of a powder in its non-aggregated state.Primary particle diameter can be determined using a laser-diffractionparticle size distribution analyzer. In some embodiments, the particlesize analyzer can be Mastersizer 2000 manufactured by MalvernInstruments Limited.

The pharmacokinetic data disclosed herein (e.g., C_(max), T_(max),AUC_(0-t), AUC_(0-480 minutes), AUC_(0-inf), T_(1/2)) can be measuredfrom a primate, preferably a monkey, and preferably a Cynomolgus monkey,after a powder formulation disclosed herein is administered.Alternatively, the pharmacokinetic data disclosed herein (e.g., C_(max),T_(max), AUC_(0-t), AUC_(0-480 minutes), AUC_(0-inf), T_(1/2)) can bemeasured from a human subject after a powder formulation disclosedherein is administered.

Presented herein are formulations comprising dihydroergotamine (DHE), ora pharmaceutically acceptable salt thereof. Also presented herein aremethods for treating headache, for example, methods of treating migrainein a subject, e.g. in a human, comprising intranasally administeringparticular formulations comprising dihydroergotamine, or apharmaceutically acceptable salt thereof, to a subject, e.g. a human,having a headache, for example, a migraine, wherein the formulation isnot a liquid solution or a liquid spray formulation. For example,presented herein are methods for rapid onset treatment of headache,including migraine, e.g. acute treatment of migraine with or withoutaura, comprising intranasally administering the formulations presentedherein. Unless noted, such formulations are referred to herein as powderformulations.

Intranasal administration, as used herein in the context of the powderformulations presented herein, unless otherwise noted, refers toadministration whereby at least 95±5% of the powder formulation isadministered to the nasal cavity as measured by multiple path particledosimetry (MPPD) model analysis, a computational model used to estimatehuman airway particle dosimetry (see, e.g., Anjilvel, S. and Asgharian,B. (1995) Fundam. Appl. Toxicol. 28, 41-50; and National Institute forPublic Health and the Environment (RIVM) (2002) Multiple Path ParticleDosimetry Model (MPPD v 1.0): A Model for Human and Rat Airway ParticleDosimetry. Bilthoven, The Netherlands. RIVA Report 650010030), or via anAndersen Cascade Impactor.

Generally, not less than 90% of the particles in the powder formulationspresented herein have a diameter less than 150 μm, and not more than 5%of the particles in the powder formulations have a diameter less than 10μm. In addition, generally, the overall mean particle size of theparticles in the powder formulations presented herein about 15 to about30 μm, about 18 to about 25 μm, about 18 to about 20 μm, or about 20 μm.

In a particular aspect, presented herein is a method of treatingheadache, for example treating migraine e.g., a method for acutetreatment of migraine with or without aura, comprising intranasallyadministering to a human having a headache, e.g., a migraine, aformulation comprising DHE, or a pharmaceutically acceptable saltthereof, e.g., DHE mesylate, microcrystalline cellulose, and tribasiccalcium phosphate, wherein the formulation is not a liquid solution or aliquid spray formulation. Unless noted, such formulations are referredto herein as powder formulations. In a specific aspect, provided hereinare methods of treating headache, including migraine, comprisingintranasally administering powder formulations comprisingdihydroergotamine or a pharmaceutically acceptable salt thereof, e.g.,dihydroergotamine mesylate, microcrystalline cellulose with a meanparticle diameter size of about 100 μm or less, and tribasic calciumphosphate. Throughout, unless otherwise noted, “about” means within +10%of a value. For example, if it is stated that a component makes up“about 70%” of a mixture, it is implied that the component makes upwithin a range of 63% and 77% of the mixture. In addition, in instanceswherein “about” is used, it is to be understood that embodimentsinvolving the exact value associated with “about” are also contemplated.For example, when an embodiment recites “about 0.5 mg DHE,” anembodiment reciting “0.5 mg DHE” is also contemplated and is describedherein.

In yet another aspect, provided herein are methods of treating headache,including migraine, comprising intranasally administering powderformulations comprising dihydroergotamine or a pharmaceuticallyacceptable salt thereof, e.g., dihydroergotamine mesylate, amicrocrystalline cellulose portion with a mean particle size diameter ofabout 50-55 m, e.g., 50 μm, comprising about 10% of the total weight ofthe powder formulation, a microcrystalline cellulose portion with a meanparticle size of about 20 μm comprising about 3 to about 90%, e.g., 8 toabout 90%, of the total weight of the powder formulation and,optionally, a fluidizing agent. In certain embodiments, the powderformulations utilized as part of the methods further comprise caffeine,e.g., anhydrous caffeine. Throughout, unless otherwise noted, percent(%) weight, in the context of the powder formulations presented herein,refers to weight per weight percent (%) (W/W %).

In another aspect, presented herein are powder formulations that can beutilized in conjunction with the methods of treating headache, includingmigraine. In a certain aspect, presented herein are powder formulationscomprising dihydroergotamine or a pharmaceutically acceptable saltthereof. In a specific aspect, provided herein are powder formulationscomprising: a) dihydroergotamine or a pharmaceutically acceptable saltthereof, e.g., dihydroergotamine mesylate; b) microcrystallinecellulose, e.g., a microcrystalline cellulose with a mean particlediameter size of about 100 μm or less; and c) tribasic calciumphosphate. In yet another aspect, provided herein are powderformulations comprising dihydroergotamine, or a pharmaceuticallyacceptable salt thereof, e.g., dihydroergotamine mesylate amicrocrystalline cellulose portion with a mean particle size diameter ofabout 50-55 μm, e.g., 50 μm, comprising about 10% of the total weight ofthe powder formulation, a microcrystalline cellulose portion with a meanparticle size of about 20 μm comprising about 3% to about 90%, e.g.,about 8 to about 90%, of the total weight of the powder formulation and,optionally, a fluidizing agent. In certain embodiments, the powderformulations further comprise caffeine, e.g., anhydrous caffeine.

In certain embodiments, greater than or equal to about 90% of theparticles in the powder formulation have a diameter less than 150 μm. Inother embodiments the overall mean particle size of the formulation isabout 15 to about 30 μm, about 18 to about 25 μm, about 18 to about 20μm, or about 20 μm. In further embodiments, less than or equal to about5% of the particles in the powder formulation have a diameter less than10 μm. In yet other embodiments, greater than or equal to about 90% ofthe particles in the power formulation have a diameter less than 150 μm;and the overall mean particle size of the formulation is about 15 toabout 30 μm, about 18 to about 25 μm, about 18 to about 20 μm, or about20 μm; and less than or equal to about 5% of the particles in the powderformulation have a diameter less than 10 μm.

5.1 Dihydroergotamine

Dihydroergotamine (DHE) is an ergot alkaloid having a structure asfollows:

The methods and formulations presented herein can utilize DHE and anypharmaceutically acceptable salt, hydrate, polymorph, isomer,diastereomer, prodrug, metabolite, ion pair complex, or chelate thereof.

In certain embodiments, the methods and formulations presented hereincomprise a pharmaceutically acceptable salt of DHE. In embodimentswherein a pharmaceutically acceptable salt of DHE is utilized, thepharmaceutically acceptable salt of DHE may be used instead of or inaddition to DHE in any or all of the methods and compositions presentedherein.

A pharmaceutically acceptable salt of DHE can be formed using apharmaceutically acceptable non-toxic acid or base, including aninorganic acid or base, or an organic acid or base. In specificembodiments, a pharmaceutically acceptable salt of DHE that can beutilized in connection with the methods and formulations presentedherein is a pharmaceutically acceptable salt derived from acidsincluding, but not limited to, the following: acetic, alginic,anthranilic, benzenesulfonic, benzoic, camphorsulfonic, citric,ethenesulfonic, formic, fumaric, furoic, galacturonic, gluconic,glucuronic, glutamic, glycolic, hydrobromic, hydrochloric, isethionic,lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic,pantothenic, phenylacetic, phosphoric, propionic, salicylic, stearic,succinic, sulfanilic, sulfuric, tartaric acid, or p-toluenesulfonicacid. In one embodiment the pharmaceutically acceptable salt of DHE is asalt of methanesulfonic acid. An alternative nomenclature of themethanesulfonic acid salt of DHE is DHE mesylate.

For further description of pharmaceutically acceptable salts that can beused in the methods described herein see, for example, S. M. Barge etal., “Pharmaceutical Salts,” 1977, J. Pharm. Sci. 66:1-19, which isincorporated herein by reference in its entirety.

The mean particle size of the DHE or pharmaceutically acceptable salt ofDHE, e.g, DHE mesylate, utilized can be less than about 100 μm, forexample, about 95, 90, 85, 80, 75, 70, 65, 60, 55, 50, 45, 40, 35, 30,25, 20, 15, 10, 5 μm or less. The mean particle size of the DHE orpharmaceutically acceptable salt of DHE, e.g, DHE mesylate, utilized canbe about 5-100 μm, for example, for example, about 5-90, 5-80, 5-70,5-60, 5-50, 5-40, 5-30, 5-20, 5-10, 10-90, 10-80, 10-70, 10-60, 10-50,10-40, 10-30, 10-20, 20-90, 20-80, 20-70, 20-60, 20-50, 20-40, 20-30,30-90, 30-80, 30-70, 30-60, 30-50, 30-40, 40-90, 40-80, 40-70, 40-60,40-50, 50-90, 50-80, 50-70, 50-60, 60-90, 60-80, 60-70, 70-90, 70-80, or80-90 μm. The mean particle size of the DHE or pharmaceuticallyacceptable salt of DHE, e.g, DHE mesylate, utilized can be about 5.0,5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10, 11, 12, 13, 14, 15, 16,17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90,95, or 100 μm. Moreover, generally, not less than 90% of the DHE orpharmaceutically acceptable salt of DHE, e.g., DHE mesylate, particlesin the powder formulations presented herein have a diameter less than150 μm, and not more than 5% of the particles in the powder formulationhave a diameter less than 5 μm. In addition, generally, the overall meanparticle size of the DHE particles in the powder formulations presentedherein about 15 to about 30 μm, about 18 to about 25 μm, about 18 toabout 20 μm, or about 20 μm.

In some embodiments, the total weight of the powder formulationcomprises about 0.4 to about 46%, or about 0.4 to about 23% or about 0.4to about 9%, or about 2 to about 9%, or about 4 to about 9% of DHE. Inother embodiments, the total weight of the powder formulation comprisesabout 0.3 to about 37%, or about 0.3 to about 18% or about 0.3 to about7%, or about 2 to about 7%, or about 3 to about 9% of DHE or apharmaceutically acceptable salt thereof.

5.2 Methods of Treating Headache

Presented herein are methods for treating headache, for example, methodsof treating migraine in a subject, e.g. in a human, comprisingintranasally administering particular formulations comprisingdihydroergotamine, or a pharmaceutically acceptable salt thereof, to asubject, e.g. a human, having a headache, for example, a migraine. Forexample, presented herein are methods for rapid onset treatment ofheadache, including migraine, e.g. acute treatment of migraine with orwithout aura, comprising intranasally administering the formulationspresented herein.

In a particular aspect, provided herein are methods of treatingheadache, including migraine, comprising intranasally administeringpowder formulations comprising dihydroergotamine or a pharmaceuticallyacceptable salt thereof. In a specific aspect, provided herein aremethods of treating headache, including migraine, comprisingintranasally administering powder formulations comprisingdihydroergotamine or a pharmaceutically acceptable salt thereof, e.g.,dihydroergotamine mesylate, microcrystalline cellulose with a meanparticle diameter size of about 100 μm or less, and tribasic calciumphosphate. In yet another aspect, provided herein are methods oftreating headache, including migraine, comprising intranasallyadministering powder formulations comprising dihydroergotamine or apharmaceutically acceptable salt thereof, e.g., dihydroergotaminemesylate a microcrystalline cellulose portion with a mean particle sizediameter of about 50-55 μm, e.g., about 50 μm, comprising about 10% ofthe total weight of the powder formulation, a microcrystalline celluloseportion with a mean particle size of about 20 μm comprising about 3 toabout 90%, e.g., about 8 to about 90%, of the total weight of the powderformulation and, optionally, a fluidizing agent. In certain embodiments,the powder formulations utilized as part of the methods further comprisecaffeine, e.g., anhydrous caffeine.

In certain embodiments, the headache treated by the methods providedherein is a cluster headache, chronic daily headache, or migraine,including adult migraine or pediatric migraine. The migraine can bemigraine with aura or migraine without aura. In particular embodiments,the methods presented herein are methods for acute treatment of a humanhaving a migraine with or without aura. In other embodiments, themethods presented herein are methods for chronic treatment of migrainewith or without aura.

“Treating,” as used herein, refers to the amelioration of at least onesymptom of the disorder being treated. Thus, the methods of treatingheadache, for example migraine, presented herein ameliorate at least onesymptom of the headache, for example migraine. In certain embodiments,the methods of treating headache, for example migraine, presented hereinreduce at least one symptom of the headache, for example migraine. Inother embodiments, the methods of treating headache, for examplemigraine, presented herein eliminate at least one symptom of theheadache, for example, migraine.

Symptoms of headache, e.g., cluster headache, chronic daily headache ormigraine, include pain. Symptoms of migraine can also include, forexample, nausea, vomiting, photophobia, phonophobia, osmophobia(aversion to, or hypersensitivity to, odors), vertigo, and/or allodynia.In certain embodiments, the methods of treating headache, for examplemigraine, presented herein ameliorate at least one such symptom of theheadache, for example migraine. In particular embodiments, the methodsof treating headache, for example migraine, presented herein reduce atleast one such symptom of the headache, for example migraine. In otherparticular embodiments, the methods of treating headache, for examplemigraine, presented herein eliminate at least one such symptom of theheadache, for example, migraine.

In specific embodiments, the methods of treating migraine ameliorate atleast one of pain, nausea, phonophobia or photophobia. In other specificembodiments, such methods ameliorate at least two, three or all four ofsaid symptoms.

In some embodiments, the headache has a severity of more than about anyof 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 on a scale of 0 to 10. In certainembodiments, the methods of treating a headache, for example migraine,presented herein ameliorate at least one symptom of a headache, forexample a migraine, having a severity of more than about any of 1, 2, 3,4, 5, 6, 7, 8, 9, or 10 on a scale of 0 to 10. In certain embodiments,the methods of treating headache, for example migraine, presented hereinreduce the severity of a headache, for example a migraine, having aseverity of more than about any of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 on ascale of 0 to 10.

In certain embodiments, the intensity of headache pain, for example,pain associated with migraine, can be measured according to a 4-pointseverity scale (0=no pain, 1=mild, 2=moderate, 3=severe). In certainembodiments, the methods of treating headache, for example migraine,presented herein reduce the severity of headache pain, for example painassociated with migraine, by at least one point on such a 4-pointseverity scale.

In certain embodiments, the methods of treating migraine presentedherein ameliorate at least one symptom of the migraine, e.g., ameliorateat least one of pain, nausea, phonophobia, or photophobia. The symptomor symptoms can, for example, be evaluated via a four point severityscale as follows: 0=none 1=mild symptom, not interfering with normaldaily activities 2=moderate symptom, causing some restriction to normalactivities 3=severe, leading to inability to perform normal dailyactivities. Alternatively, or additionally, a symptom or symptoms,including the four listed above, can be evaluated via a four-pointfunctional disability scale that assesses the level of impairment asymptom has on a patient's ability to perform usual daily activities, asfollows: 0=not at all impaired 1=slightly impaired 2=moderately impaired3=severely or completely impaired See, Cephalalgia 1991; 11:1-12.

In certain embodiments, the methods of treating headache, for examplemigraine, presented herein ameliorate at least one symptom of theheadache, for example migraine, within 10, 15, 20, 25, 30 or 45 minutesof intranasally administering a powder formulation presented herein. Inother embodiments, the methods of treating headache, for examplemigraine, presented herein ameliorate at least one symptom of theheadache, for example migraine, within 1, 1.5, 2, 2.5, 3, or 4 hours ofintranasally administering a powder formulation presented herein. Inparticular embodiments, methods of treating headache, for examplemigraine, presented herein the amelioration of at least one symptom ofthe headache, for example migraine, is sustained for about 3, 4, 5, 6,8, 12, 18, 36, or 48 hours.

With respect to the microcrystalline cellulose component of the powderformulations presented herein, generally, acceptable microcrystallinecellulose can include microcrystalline cellulose obtained by decomposingcellulose materials such as pulp by either or both of acid and alkalinehydrolyses, then purifying the hydrolysate, and crushing or grinding itbefore, during, or after drying. Microcrystalline cellulose ofparticular mean particle diameter size can be obtained, for example, viaappropriate processing, e.g., via fine grinding using a high-speedrotary impact mill or air attrition mill as necessary, and size sorting.In certain embodiments, microcrystalline cellulose components utilizedas part of the microcellulose of the powder formulations presentedherein can include products available under the trade names of Ceolus®PH-F20JP, Ceolus® PH-301, Ceolus®PH-101, Ceolus® PH-102, and Ceolus®PH-302 (available from Asahi Kasei Corporation), and Avicel® PH-105,Avicel®PH-101, Avicel®PH-102, Avicel®PH-301, and Avicel®PH-302(available from FMC Biopolymer Corporation). In a particular embodiment,powder formulations that can be used in conjunction with the methods andcompositions presented herein can comprise Ceolus® PH-F20JP and Ceolus®PH-301.

Mean particle size diameters, for example, the mean particle sizediameters of the microcrystalline portions of the powder formulationsdescribed herein, can be determined using standard techniques, forexample, via a laser-diffraction particle size distribution analyzer orvia sorting methods. The mean particle diameter size refers to adiameter that divides particles into two groups of equal numbers: agroup with greater diameters and a group with smaller diameters. Themean diameter size determined using a laser-diffraction particle sizedistribution analyzer corresponds to 50% volume in a determinedcumulative particle size distribution curve. The mean particle diametersize can, for example, be determined by a sorting method thatcorresponds to 50 (W/W) % on a cumulative particle size distributioncurve that can be obtained by sorting an appropriate amount of theparticle being assessed, for an appropriate time, e.g., ten minutes, onan electromagnetic sieve shaker, using standard sieves and weighing thesample remaining on each sieve.

With respect to tribasic calcium phosphate (also known ashydroxyapatite), any pharmaceutically acceptable tribasic calciumphosphate can be used in conjunction with the methods and compositionspresented herein. In certain embodiments, the tribasic calcium phosphateutilized has an average particle diameter of about 10-100 μm, forexample, about 10 to 75 μm, about 10 to 50 μm, about 10-30 μm, or about10 μm. Moreover, generally, not less than 90% of the tribasic calciumphosphate particles in the powder formulations presented herein have adiameter less than 150 μm, and not more than 5% of the particles in thepowder formulation have a diameter less than 10 μm. In addition,generally, the overall mean particle size of the tribasic calciumphosphate particles in the powder formulations presented herein about 15to about 30 μm, about 18 to about 25 μm, about 18 to about 20 μm, orabout 20 μm.

In certain embodiments, greater than or equal to about 90% of thetribasic calcium phosphate particles have a diameter less than 150 μm.In other embodiments the overall mean particle size of the tribasiccalcium phosphate particles is about 15 to about 30 μm, about 18 toabout 25 μm, about 18 to about 20 μm, or about 20 μm. In furtherembodiments, less than or equal to about 5% of the tribasic calciumphosphate particles have a diameter less than 10 μm. In yet otherembodiments, for the tribasic calcium phosphate particles, greater thanor equal to about 90% of the particles have a diameter less than 150 μm;and the overall mean particle size is about 15 to about 30 μm, about 18to about 25 μm, about 18 to about 20 μm, or about 20 μm; and less thanor equal to about 5% of the particles have a diameter less than 10 μm.

The powder formulations described herein can be made using standardtechniques. For example, the components of the powder formulations canbe mixed while applying a shearing force, e.g., via a high shearmixer/stirrer. Alternatively, for example, the components of the powderformulations can be homogeneously mixed using, e.g., a mortar orV-blender. The order of mixing is not critical to the productionprocess. See Example 1, below, for representative, non-limited examplesof methods for the production of powder formulations as presentedherein.

The powder formulations can be intranasally administered utilizing anytechniques known in the art. For example, the formulations can beadministered utilizing a dispenser, for example a single use dispenseror a multi-use dispenser. In certain embodiments the powder formulationsare administered using a device such as, for example, a device asdescribed in US 2011/0045088 or in WO 2012/105236, each of which isincorporated herein by reference for its disclosure of devices that canbe utilized to intranasally administer powder formulations to a primate,for example, to a human. In specific embodiments, the device used toadminister the powder formulation is a Fit-lizer™ (SNBL, LTD) intranasaldispenser device.

In certain specific embodiments, the powder formulations presentedherein are encapsulated prior to administration. For example, the powderformulations presented herein can be encapsulated in unit dose form. Incertain embodiments, the encapsulated powder formulations are releasedfrom the capsule prior to administration. In other embodiments, thepowder formulations are released from the capsule upon administration.Powder formulations can, for example, be intranasally administeredutilizing devices designed to accept and delivery powder formulationsthat have been encapsulated. In certain embodiments, the fill weight ofthe capsule comprises an appropriate excess amount of the powderformulation such that the desired dose is administered, taking intoaccount the particular administration device being utilized.

In one aspect, presented herein is a method of treating headachecomprising: intranasally administering to a human having a headache apowder formulation comprising: a) DHE, or a pharmaceutically acceptablesalt thereof, wherein the total dose of DHE being administered is about0.1-10.0 mg; b) a microcrystalline cellulose component with a meanparticle size diameter of about 100 μm or less; and c) tribasic calciumphosphate. Herein, unless otherwise noted, “the total dose of DHE beingadministered” and like phrasing means the total amount of parent DHE inthe DHE form, e.g., amount of DHE free base in a pharmaceuticallyacceptable DHE salt, being administered. In a particular embodiment, thepowder formulation comprises DHE mesylate, and the total amount of DHEfree base of the DHE mesylate being administered is about 0.1-10.0 mg.

In certain embodiments of such a method, the powder formulation isadministered to a single nostril of the human having a headache. Inother embodiments of the method, a portion of the powder formulation isadministered to each nostril of the human. For example, in a specificembodiment of the method, about half of the powder formulation isadministered to one nostril and about half of the powder formulation isadministered to the other nostril of the human having a headache.

In another aspect, presented herein is a method of treating migrainecomprising: intranasally administering to a human having a migraine apowder formulation comprising: a) DHE, or a pharmaceutically acceptablesalt thereof, wherein the total dose of DHE being administered is about0.1-10.0 mg; b) a microcrystalline cellulose component with a meanparticle size diameter of about 100 μm or less; and c) tribasic calciumphosphate. In a particular embodiment, the powder formulation comprisesDHE mesylate. In certain embodiments of the method, the powderformulation is administered to a single nostril of the human having amigraine. In other embodiments of the method, a portion of the powderformulation is administered to each nostril of the human having amigraine. For example, in a specific embodiment, about half of thepowder formulation is administered to one nostril and about half of thepowder formulation is administered to the other nostril of the humanhaving a migraine.

In yet another embodiment of such a method of treating headache,including migraine, the microcrystalline cellulose component of theformulation comprises a first microcrystalline cellulose portion with amean particle diameter size of about 30 μm or less, and a secondmicrocrystalline cellulose portion with a mean particle size diameter ofabout 30-100 μm. In a particular embodiment of such a method, the firstmicrocrystalline cellulose portion has a mean particle diameter size ofabout 15-30 μm. In a specific embodiment of such a method, the firstmicrocrystalline cellulose portion has a mean particle diameter size ofabout 18-20 μm. In yet another specific embodiment of such a method, thefirst microcrystalline cellulose portion has a mean particle diametersize of about 20 μm. In another particular embodiment of such a method,the second microcrystalline cellulose portion has a mean particlediameter size of about 45-65 μm. In a specific embodiment of such amethod, the second microcrystalline cellulose portion has a meanparticle diameter size of about 45-55 μm. In another specific embodimentof such a method, the second microcrystalline cellulose portion has amean particle diameter size of about 50-55 μm. In another specificembodiment of such a method, the second microcrystalline celluloseportion has a mean particle diameter size of about 50 μm. In yet anotherembodiment of such a method, the first microcrystalline celluloseportion has a mean particle diameter size of about 20 μm, and the secondmicrocrystalline cellulose portion has a mean particle size diameter ofabout 50 μm. In yet other embodiments of such a method, the firstmicrocrystalline cellulose portion has a mean particle diameter size ofabout 30 μm or less, for example, about 15-30 μm, about 18-20 μm, orabout 20 μm, and the second microcrystalline cellulose portion has amean particle diameter size of about 45-65 μm, about 45-55 μm, about50-55 μm, or about 50 μm. In instances wherein the method is a methodfor treating migraine, the method can, in certain embodiments, be amethod for the acute treatment of migraine with or without aura.

In certain embodiments of such methods of treating headache, includingmigraine, the microcrystalline cellulose component of the powderformulation comprises about 10 to about 99%, e.g., about 15 to about99%, of the total weight of the formulation. In other embodiments, themicrocrystalline cellulose component of the powder formulation comprisesabout 53 to about 99%, about 76 to about 99%, about 76 to about 97%,about 90 to about 97%, or about 90 to about 95% of the total weight ofthe formulation. In some embodiments, the microcrystalline cellulosecomponent of the powder formulation comprises about 10 to about 98%,about 18 to about 98%, about 18 to about 91%, about 67 to about 91%, orabout 67 to about 83%. In further embodiments, the microcrystallinecellulose component of the powder formulation comprises about 53%, about76%, about 90%, about 95%, about 97%, or about 99% of the total weightof the formulation. In other embodiments, the microcrystalline cellulosecomponent of the powder formulation comprises about 10%, about 18%,about 66%, about 83%, about 91%, or about 98% of the total weight of theformulation.

For example, in particular embodiments, the first microcrystallinecellulose portion comprises about 3.0 to about 90%, e.g., about 8.0 toabout 90%, of the total weight of the formulation, and the secondmicrocrystalline cellulose portion comprises about 10% of the totalweight of the formulation. In other embodiments, the firstmicrocrystalline cellulose portion comprises about comprises about 43 toabout 89%, about 66 to about 89%, about 66 to about 87%, about 80 toabout 87%, or about 80 to about 85% of the total weight of theformulation, of the total weight of the formulation, and the secondmicrocrystalline cellulose portion comprises about 10% of the totalweight of the formulation. In some embodiments, the microcrystallinecellulose component of the powder formulation comprises about 1 to about88%, about 8 to about 88%, about 8 to about 81%, about 57 to about 81%,or about 57 to about 83%, and the second microcrystalline celluloseportion comprises about 10% of the total weight of the formulation. Infurther embodiments, the microcrystalline cellulose component of thepowder formulation comprises about 43%, about 66%, about 80%, about 85%,about 87%, or about 89% of the total weight of the formulation, and thesecond microcrystalline cellulose portion comprises about 10% of thetotal weight of the formulation. In other embodiments, themicrocrystalline cellulose component of the powder formulation comprisesabout 1%, about 8%, about 57%, about 73%, about 81%, or about 88% of thetotal weight of the formulation, and the second microcrystallinecellulose portion comprises about 10% of the total weight of theformulation.

In certain embodiments of the methods of treating headache, includingmigraine, the tribasic calcium phosphate comprises about 0.5-1.0% of thetotal weight of the formulation. In specific embodiments of the methodsof treating headache, including migraine, the tribasic calcium phosphatecomprises about 0.8% of the total weight of the formulation.

In another aspect, the powder formulations utilized as part of themethods of treating headache, including migraine, further comprisecaffeine, for example, anhydrous caffeine In specific embodiments, thepowder formulations utilized as part of the methods of treatingheadache, including migraine, comprise about 1-60%, about 1-25%, about10-60%, or about 10-25% caffeine, for example, anhydrous caffeine. Inother embodiments, the powder formulations utilized as part of themethods of treating headache, including migraine, comprise about 1%,about 5%, about 6%, about 10%, about 12%, about 20%, about 23%, about39%, about 48%, about 50%, or about 58% caffeine.

While the particle size of the caffeine utilized as part of the powderformulations described herein is not particularly critical, the meanparticle size of the caffeine, e.g., anhydrous caffeine, is generallyabout 10-100 μm, for example, about 10 to 75 μm, about 10 to 50 μm,about 10-30 μm, about 10-20 μm, about 15-20 μm, about 10 μm, about 15μm, about 16 μm, about 17 μm, about 18 μm, about 19 μm, or about 20 μm.Moreover, generally, not less than 90% of the caffeine, e.g., anhydrouscaffeine, particles in the powder formulations presented herein have adiameter less than 150 μm, and not more than 5% of the caffeineparticles in the powder formulation have a diameter less than 10 μm. Inaddition, generally, the overall mean particle size of the caffeine,e.g., anhydrous caffeine, particles in the powder formulations presentedherein about 15 to about 30 μm, about 18 to about 25 μm, about 18 toabout 20 μm, or about 20 μm.

In particular embodiments of such methods of treating headache,including migraine, the total dose of DHE administered is about 0.1-5.0mg. In certain other embodiments, the total dose of DHE administered isabout 0.5-5.0 mg. In certain other embodiments, the total dose of DHEadministered is about 0.5-3.0 mg. In certain other embodiments, thetotal dose of DHE administered is about 1.0-2.0 mg. In particularembodiments of such methods, the total dose of DHE administered is about0.1 mg, about 0.5 mg, about 1.0 mg, about 1.5 mg, about 2.0 mg, about3.0 mg, about 4.0 mg, about 5.0 mg, about 7.5 mg, or about 10.0 mg. Incertain embodiments, the total dose is administered into a singlenostril. In other embodiments, a portion of the total dose isadministered into each nostril. In yet other embodiments, about half ofthe total dose is administered into one nostril and the remaining halfis administered into the other nostril.

In specific embodiments of such a method of treating headache, includingmigraine, the total amount of the powder formulation administered is 5,10, 15, 20, 25, 30, 35, 40, 45, or 50 mg. In certain embodiments, thetotal amount of the powder formulation is administered into a singlenostril. In other embodiments, a portion of the total amount of thepowder formulation is administered into each nostril. In yet otherembodiments, about half of the total amount of the powder formulation isadministered into one nostril and the remaining half is administeredinto the other nostril.

In particular embodiments wherein such methods of treating headache aremethods of treating migraine, the methods can include a method for theacute treatment of migraine with or without aura.

In certain embodiments, the methods of treating headache, includingmigraine, comprise administering the powder formulation such that themean T_(max) of DHE is about 10-50 minutes. In other embodiments, themean T_(max) of DHE is about 10-30 minutes. In further embodiments, themean T_(max) of DHE is about 5-50 minutes. In yet further embodiments,the mean T_(max) of DHE is about 5-30 minutes. In further embodiments,the mean T_(max) of DHE is about 2-50 minutes. In yet furtherembodiments, the mean T_(max) of DHE is about 2-30 minutes. In otherembodiments, the methods of treating headache, including migraine,comprise administering the powder formulation such that the mean C_(max)of DHE is about 0.5-100 ng/mL. In yet other embodiments, such methods oftreating headache, including migraine, utilizing about 0.1-1.0 mg DHEcomprise administering the powder formulation such that the meanAUC_(0-inf) of DHE is about 1-500 ng·h/mL. In further embodiments, themean AUC_(0-30 min) of DHE is about 1-500 ng·h/mL. In yet otherembodiments, the methods of treating headache, including migraine,comprise administering the powder formulation such that the mean T_(1/2)of DHE is about 110-260 minutes. In yet other embodiments, the methodsof treating headache, including migraine, comprise administering theintersubject variability in DHE C_(max) is less than 30%.

In a particular aspect, presented herein is a method of treatingheadache, including migraine, comprising: intranasally administering toa human having a headache, e.g., migraine, a powder formulationcomprising: a) DHE, or a pharmaceutically acceptable salt thereof,wherein the total dose of DHE being administered is about 0.1-2.0 mg; b)a microcrystalline cellulose component comprising a firstmicrocrystalline cellulose portion with a mean particle size of about 30μm or less, for example, about 15-30 μm, about 18-20 μm, or about 20 μm,and a second microcrystalline cellulose portion with a mean particlesize diameter of about 45-65 μm, about 45-55 μm, about 50-55 μm, orabout 50 μm, wherein the first microcrystalline cellulose portioncomprises about 45 to about 90%, e.g., about 50 to about 90%, of thetotal weight of the formulation, and the second microcrystalline portioncomprises about 10% of the total weight of the formulation; and c)tribasic calcium phosphate comprising about 0.5-1.0%, e.g., about 0.8%,of the total weight of the formulation.

In a specific embodiment of such a method, the powder formulationcomprises DHE mesylate. In another specific embodiment of such a method,the powder formulation is administered to a single nostril of the humanhaving a headache, e.g., migraine. In yet another specific embodiment ofsuch a method, a portion of the powder formulation is administered toeach nostril of the human having a headache, e.g. headache. For example,in a specific embodiment, about half of the powder formulation isadministered to one nostril and about half of the powder formulation isadministered to the other nostril of the human having a headache, e.g.headache.

In instances wherein such a method is a method of treating migraine, themethod can be a method of acute treatment of migraine with or withoutaura.

In yet another particular embodiment of such a method of treatingheadache, including migraine, the powder formulation further comprisescaffeine, for example, about 1-25% caffeine, e.g., anhydrous caffeine.

In specific embodiments of such a method of treating headache, includingmigraine, the total amount of the powder formulation administered is 5,10, 15, 20, 25, 30, 35, 40, 45, or 50 mg. In certain embodiments, thetotal amount of the powder formulation is administered into a singlenostril. In other embodiments, a portion of the total amount of thepowder formulation is administered into each nostril. In yet otherembodiments, about half of the total amount of the powder formulation isadministered into one nostril and the remaining half is administeredinto the other nostril.

In a particular embodiment of such a method of treating headache,including migraine utilizing a powder formulation comprising about0.1-2.0 mg DHE, the powder formulation is administered such that themean T_(max) of DHE is about 10-50 minutes. In another embodiment, thepowder formulation is administered such that the mean T_(max) of DHE isabout 2-50 minutes. In another embodiment, the powder formulation isadministered such that the mean T_(max) of DHE is about 2-30 minutes. Inanother particular embodiment, the powder formulation is administeredsuch that the mean C_(max) of DHE is about 0.5-40 ng/mL. In yet anotherparticular embodiment, the powder formulation is administered such thatthe mean AUC_(0-inf) of DHE is about 1-200 ng·h/mL. In another specificembodiment of such a method of treating headache, including migraine,the powder formulation is administered such that the mean T_(1/2) of DHEis about 100-300 minutes. In still another embodiment of such a methodof treating headache, including migraine, the intersubject variabilityin DHE C_(max) is less than 30%.

In another particular aspect, presented herein is a method of treatingheadache, including migraine, comprising: intranasally administering toa human having a headache, e.g., migraine, a powder formulationcomprising: a) DHE, or a pharmaceutically acceptable salt thereof, e.g.,DHE mesylate, wherein the total dose of DHE administered is about 0.1mg; b) a microcrystalline cellulose component comprising a firstmicrocrystalline cellulose portion with a mean particle size of about 30μm or less, for example, about 15-30 μm, about 18-20 μm, or about 20 μm,and a second microcrystalline cellulose portion with a mean particlesize diameter of about 45-65 μm, for example, about 45-55 μm or about50-55 μm, e.g., about 50 μm, wherein the first microcrystallinecellulose portion comprises about 80 to about 90%, e.g., about 85 toabout 90%, of the total weight of the formulation, and the secondmicrocrystalline portion comprises about 10% of the total weight of theformulation; and c) tribasic calcium phosphate comprising about0.5-1.0%, e.g., about 0.8%, of the total weight of the formulation. Inyet another particular embodiment of such a method of treating headache,including migraine, the powder formulation further comprises caffeine,for example, about 1-2% caffeine, e.g. anhydrous caffeine.

In another specific embodiment of such a method, the powder formulationis administered to a single nostril of the human having a migraine. Inyet another specific embodiment of such a method, a portion of thepowder formulation is administered to each nostril of the human having aheadache, e.g., migraine. For example, in a specific embodiment, abouthalf of the powder formulation is administered to one nostril and abouthalf of the powder formulation is administered to the other nostril ofthe human having a headache, e.g., migraine. In specific embodiments ofsuch a method of treating headache, including migraine, the total amountof the powder formulation administered is about 5, 10, 15, 20, 25, 30,35, 40, 45, or 50 mg, into a single or into both nostrils.

In instances wherein such a method is a method of treating migraine, themethod can be acute treatment of migraine with or without aura.

In a particular embodiment of such a method of treating headache,including migraine, utilizing a powder formulation comprising about 0.1mg DHE, the powder formulation is administered such that the meanT_(max) of DHE is about 10-30 minutes. In another embodiment, the powderformulation is administered such that the mean T_(max) of DHE is about2-50 minutes. In another embodiment, the powder formulation isadministered such that the mean T_(max) of DHE is about 2-30 minutes. Inanother particular embodiment of such a method of treating headache,including migraine, the powder formulation is administered such that themean C_(max) of DHE is about 0.1-6 ng/mL. In another embodiment of sucha method of treating headache, including migraine, the powderformulation is administered such that the mean AUC_(0-inf) of DHE isabout 1-15 ng·h/mL. In another embodiment of such a method of treatingheadache, including migraine, the powder formulation is administeredsuch that the mean T_(1/2) of DHE is about 100-300 minutes. In yetanother particular embodiment of such a method of treating headache,including migraine, the powder formulation is administered such that themean T_(max) of DHE is about 2-30 minutes, the mean C_(max) of DHE isabout 0.1-6 ng/mL, the mean AUC_(0-inf) of DHE is about 1-15 ng·h/mL,and the mean T_(1/2) of DHE is about 100-300 minutes. In still anotherembodiment of such a method of treating headache, including migraine,the intersubject variability in DHE C_(max) is less than 30%.

In yet another aspect, presented herein is a method of treatingheadache, including migraine, comprising: intranasally administering toa human having a headache, e.g, migraine, a powder formulationcomprising: a) DHE, or a pharmaceutically acceptable salt thereof, e.g.,DHE mesylate, wherein the total dose of DHE being administered is about0.5 mg; b) a microcrystalline cellulose component comprising a firstmicrocrystalline cellulose portion with a mean particle size of about 30μm or less, for example, about 15-30 μm, about 18-20 μm, or about 20 μm,and a second microcrystalline cellulose portion with a mean particlesize diameter of about 45-65 μm, for example, about 45-55 μm or about50-55 μm, e.g., about 50 μm, wherein the first microcrystallinecellulose portion comprises about 75 to about 90%, e.g., about 80 toabout 90%, of the total weight of the formulation, and the secondmicrocrystalline portion comprises about 10% of the total weight of theformulation; and c) tribasic calcium phosphate comprising about0.5-1.0%, e.g., about 0.8%, of the total weight of the formulation. Inyet another particular embodiment of such a method of treating headache,including migraine, the powder formulation further comprises caffeine,for example, about 5-10% caffeine, e.g. anhydrous caffeine.

In another specific embodiment of such a method, the powder formulationis administered to a single nostril of the human having a headache,e.g., migraine. In yet another specific embodiment of such a method, aportion of the powder formulation is administered to each nostril of thehuman having a headache, e.g., migraine. For example, in a specificembodiment, about half of the powder formulation is administered to onenostril and about half of the powder formulation is administered to theother nostril of the human having a headache, e.g., migraine. Inspecific embodiments of such a method of treating headache, includingmigraine, the total amount of the powder formulation administered isabout 5, 10, 15, 20, 25, 30, 35, 40, 45, or 50 mg, into a single or intoboth nostrils.

In a specific embodiment of such a method, the method is a method forthe acute treatment of migraine with or without aura.

In a particular embodiment of such a method of treating headache,including migraine, comprises utilizing a powder formulation comprisingabout 0.5 mg DHE, the powder formulation is administered such that themean T_(max) of DHE is about 10-50 minutes. In another embodiment, thepowder formulation is administered such that the mean T_(max) of DHE isabout 2-50 minutes. In another embodiment, the powder formulation isadministered such that the mean T_(max) of DHE is about 2-30 minutes. Inanother particular embodiment of such a method of treating headache,including migraine, the powder formulation is administered such that themean C_(max) of DHE is about 1.0-15 ng/mL. In another embodiment of sucha method of treating headache, including migraine, the powderformulation is administered such that the mean AUC_(0-inf) of DHE isabout 10-50 ng·h/mL. In another embodiment of such a method of treatingheadache, including migraine, the powder formulation is administeredsuch that the mean T_(1/2) of DHE is about 100-300 minutes. In yetanother particular embodiment of such a method of treating headache,including migraine, the powder formulation is administered such that themean T_(max) of DHE is about 2-50 minutes, the mean C_(max) of DHE isabout 1.0-15 ng/mL, the mean AUC_(0-inf) of DHE is about 10-50 ng·h/mL,and the mean T_(1/2) of DHE is about 100-300 minutes. In still anotherembodiment of such a method of treating headache, including migraine,the intersubject variability in DHE C_(max) is less than 30%.

In yet another aspect, presented herein is a method of treatingheadache, including migraine, comprising: intranasally administering toa human having a headache, e.g., migraine a powder formulationcomprising: a) DHE, or a pharmaceutically acceptable salt thereof, e.g.,DHE mesylate, wherein the total dose of DHE being administered is about1.0 mg; b) a microcrystalline cellulose component comprising a firstmicrocrystalline cellulose portion with a mean particle size of about 30μm or less, for example, about 15-30 μm, about 18-20 μm, or about 20 μm,and a second microcrystalline cellulose portion with a mean particlesize diameter of about 45-65 μm, for example, about 45-55 μm or about50-55 μm, e.g., about 50 μm, wherein the first microcrystallinecellulose portion comprises about 65 to about 90%, e.g., about 70 toabout 90%, of the total weight of the formulation, and the secondmicrocrystalline portion comprises about 10% of the total weight of theformulation; and c) tribasic calcium phosphate comprising about0.5-1.0%, e.g., about 0.8%, of the total weight of the formulation. Inyet another particular embodiment of such a method of treating migraine,the powder formulation further comprises caffeine, for example, about10-15% caffeine, e.g. anhydrous caffeine.

In another specific embodiment of such a method, the powder formulationis administered to a single nostril of the human having a headache,e.g., migraine. In yet another specific embodiment of such a method, aportion of the powder formulation is administered to each nostril of thehuman having a headache, e.g., migraine. For example, in a specificembodiment, about half of the powder formulation is administered to onenostril and about half of the powder formulation is administered to theother nostril of the human having a migraine. In specific embodiments ofsuch a method of treating headache, including migraine, the total amountof the powder formulation administered is about 5, 10, 15, 20, 25, 30,35, 40, 45, or 50 mg, into a single or into both nostrils.

In a specific embodiment of such a method, the method is a method forthe acute treatment of migraine with or without aura.

In a particular embodiment of such a method of treating headache,including migraine, utilizing a powder formulation comprising about 1.0mg DHE, the powder formulation is administered such that the meanT_(max) of DHE is about 10-50 minutes. In another embodiment, the powderformulation is administered such that the mean T_(max) of DHE is about2-50 minutes. In another embodiment, the powder formulation isadministered such that the mean T_(max) of DHE is about 2-30 minutes. Inanother particular embodiment of such a method of treating headache,including migraine, the powder formulation is administered such that themean C_(max) of DHE is about 2.0-20 ng/mL. In another embodiment of sucha method of treating headache, including migraine, the powderformulation is administered such that the mean AUC_(0-inf) of DHE isabout 15-110 ng·h/mL. In another embodiment of such a method of treatingheadache, including migraine, the powder formulation is administeredsuch that the mean T_(1/2) of DHE is about 100-300 minutes. In yetanother particular embodiment of such a method of treating headache,including migraine, the powder formulation is administered such that themean T_(max) of DHE is about 2-50 minutes, the mean C_(max) of DHE isabout 2.0-20 ng/mL, the mean AUC_(0-inf) of DHE is about 15-110 ng·h/mL,and the mean T_(1/2) of DHE is about 100-300 minutes. In still anotherembodiment of such a method of treating migraine, the intersubjectvariability in DHE C_(max) is less than 30%.

In yet another aspect, presented herein is a method of treatingheadache, including migraine, comprising: intranasally administering toa human having a migraine a powder formulation comprising: a) DHE, or apharmaceutically acceptable salt thereof, e.g., DHE mesylate, whereinthe total dose of DHE is about 2.0 mg; b) a microcrystalline cellulosecomponent comprising a first microcrystalline cellulose portion with amean particle size of about 30 μm or less, for example, about 15-30 μm,about 18-20 μm, or about 20 μm, and a second microcrystalline celluloseportion with a mean particle size diameter of about 45-65 μm, forexample, about 45-55 μm or about 50-55 μm, e.g., about 50 μm, whereinthe first microcrystalline cellulose portion comprises about 45 to about80%, e.g., about 50 to about 80%, of the total weight of theformulation, and the second microcrystalline portion comprises about 10%of the total weight of the formulation; and c) tribasic calciumphosphate comprising about 0.5-1.0%, e.g., about 0.8%, of the totalweight of the formulation. In yet another particular embodiment of sucha method of treating headache, including migraine, the powderformulation further comprises caffeine, for example, about 20-30%caffeine, e.g. anhydrous caffeine.

In another specific embodiment of such a method, the powder formulationis administered to a single nostril of the human having a headache,e.g., migraine. In yet another specific embodiment of such a method, aportion of the powder formulation is administered to each nostril of thehuman having a headache, e.g., migraine. For example, in a specificembodiment, about half of the powder formulation is administered to onenostril and about half of the powder formulation is administered to theother nostril of the human having a headache, e.g, migraine. In specificembodiments of such a method of treating headache, including migraine,the total amount of the powder formulation administered is about 5, 10,15, 20, 25, 30, 35, 40, 45, or 50 mg, into a single or into bothnostrils.

In a specific embodiment of such a method, the method is a method forthe acute treatment of migraine with or without aura.

In a particular embodiment of such a method of treating headache,including migraine, utilizing a powder formulation comprising about 2.0mg DHE, the powder formulation is administered such that the meanT_(max) of DHE is about 10-50 minutes. In another embodiment, the powderformulation is administered such that the mean T_(max) of DHE is about2-50 minutes. In another embodiment, the powder formulation isadministered such that the mean T_(max) of DHE is about 2-30 minutes. Inanother particular embodiment of such a method of treating headache,including migraine, the powder formulation is administered such that themean C_(max) of DHE is about 2.0-50 ng/mL. In another embodiment of sucha method of treating headache, including migraine, the powderformulation is administered such that the mean AUC_(0-inf) of DHE isabout 15-200 ng·h/mL. In another embodiment of such a method of treatingheadache, including migraine, the powder formulation is administeredsuch that the mean T_(1/2) of DHE is about 100-300 minutes. In yetanother particular embodiment of such a method of treating headache,including migraine, the powder formulation is administered such that themean T_(max) of DHE is about 2-50 minutes, the mean C_(max) of DHE isabout 2.0-50 ng/mL, the mean AUC_(0-inf) of DHE is about 15-200 ng·h/mL,and the mean T_(1/2) of DHE is about 100-300 minutes. In still anotherembodiment of such a method of treating headache, including migraine,the intersubject variability in DHE C_(max) is less than 30%.

In one aspect, presented herein is a method of treating headache,including migraine, comprising: intranasally administering to a humanhaving a headache a powder formulation comprising: a) DHE, or apharmaceutically acceptable salt thereof, wherein the total dose of DHEbeing administered is about 0.1-10.0 mg; b) a microcrystalline cellulosecomponent comprising a first microcrystalline cellulose portion with amean particle size diameter of about 30 μm or less, for example, about15-30 μm, about 18-20 μm, or about 20 μm, and a second microcrystallinecellulose portion with a mean particle size diameter of about 45-65 μm,for example, about 45-55 μm or about 50-55 μm, e.g., about 50 μm,wherein the first microcrystalline cellulose portion comprises about 3to about 90%, e.g., about 8 to about 90%, of the total weight of thepowder formulation of the total weight of the formulation, and thesecond microcrystalline portion comprises about 10% of the total weightof the formulation.

In a particular embodiment of such a method of treating headache,including treating migraine, the powder formulation comprises DHEmesylate. In certain embodiments of such a method, the powderformulation is administered to a single nostril of the human having aheadache, including migraine. In other embodiments of such a method, aportion of the powder formulation is administered to each nostril of thehuman having a headache, e.g., migraine. For example, in a specificembodiment of such a method, about half of the powder formulation isadministered to one nostril and about half of the powder formulation isadministered to the other nostril of the human having a headache, e.g.,migraine.

In particular embodiments of such methods of treating headache,including migraine, the total dose of DHE administered is about 0.1-5.0mg. In certain other embodiments, the total dose of DHE administered isabout 0.5-5.0 mg. In certain other embodiments, the total dose of DHEadministered is about 0.5-3.0 mg. In certain other embodiments, thetotal dose of DHE administered is about 1.0-2.0 mg. In particularembodiments of such methods, the total dose of DHE administered is about0.1 mg, about 0.5 mg, about 1.0 mg, about 1.5 mg, about 2.0 mg, about3.0 mg, about 4.0 mg, about 5.0 mg, about 7.5 mg, or about 10.0 mg. Incertain embodiments, the total dose is administered into a singlenostril. In other embodiments, a portion of the total dose isadministered into each nostril. In yet other embodiments, about half ofthe total dose is administered into one nostril and the remaining halfis administered into the other nostril.

In specific embodiments of such a method of treating headache, includingmigraine, the total amount of the powder formulation administered is 5,10, 15, 20, 25, 30, 35, 40, 45, or 50 mg. In certain embodiments, thetotal amount of the powder formulation is administered into a singlenostril. In other embodiments, a portion of the total amount of thepowder formulation is administered into each nostril. In yet otherembodiments, about half of the total amount of the powder formulation isadministered into one nostril and the remaining half is administeredinto the other nostril.

In certain embodiments of such methods of treating headache, includingmigraine, the powder formulation further comprises a fluidizing agent.Fluidizing agents include but are not limited to tribasic calciumphosphate, talc, silicon dioxide, and magnesium stearate. In someembodiments, the fluidizing agent is tribasic calcium phosphate. Incertain embodiments, the tribasic calcium phosphate comprises about0.5-1.0% of the total weight of the formulation. In specific embodimentsof the methods of treating migraine, the tribasic calcium phosphatecomprises about 0.8% of the total weight of the formulation.

In certain other embodiments, the powder formulations utilized as partof such methods of treating headache, including migraine, furthercomprise caffeine, for example, anhydrous caffeine In specificembodiments, the powder formulations utilized as part of the methods oftreating migraine comprise about 1-60% caffeine, for example, anhydrouscaffeine.

In particular embodiments, such methods are methods for the acutetreatment of migraine with or without aura.

In certain embodiments, such methods of treating headache, includingmigraine, comprise administering the powder formulation such that themean T_(max) of DHE is about 10-50 minutes. In another embodiment, thepowder formulation is administered such that the mean T_(max) of DHE isabout 2-50 minutes. In another embodiment, the powder formulation isadministered such that the mean T_(max) of DHE is about 2-30 minutes. Inother embodiments, such methods of treating headache, e.g., migraine,comprise administering the powder formulation such that the mean C_(max)of DHE is about 0.5-100 ng/mL. In yet other embodiments, the methods oftreating headache, including migraine, comprise administering the powderformulation such that the mean AUC_(0-inf) of DHE is about 4-500ng·h/mL. In yet other embodiments, the methods of treating headache,including migraine, comprise administering the powder formulation suchthat the mean T_(1/2) of DHE is about 110-260 minutes. In yet otherembodiments, the methods of treating headache, including migraine,comprise administering the intersubject variability in DHE C_(max) isless than 30%.

In yet another aspect, presented herein are methods for treatingheadache, including migraine, comprising intranasally administering to ahuman having a headache, e.g., a migraine, a powder formulationcomprising: a) DHE, or a pharmaceutically acceptable salt thereof, e.g.,DHE mesylate; b) a microcrystalline cellulose component comprising afirst microcrystalline cellulose portion having a mean particle diametersize of less than about 30 μm (e.g., about 15-30 μm, about 15-20 μm,about 18-20 μm, or about 20 μm), and a second microcrystalline celluloseportion having a mean particle diameter size of about 45-65 μm (e.g.,about 45-55 μm, about 50-55 μm, or about 50 μm); c) tribasic calciumphosphate; and, optionally d) caffeine, for example anhydrous caffeine,wherein the powder formulation contains the parameters of any of therepresentative DHE powder formulations presented, below, in Table 1.

TABLE 1 w/w % of total powder formulation DHE Dose 1^(st) MCC 2^(nd) MCC(mg) portion portion TCP Caffeine 0.1-10  38-94 5-15 0.5-1.5 0 0.1-2 75-94 5-15 0.5-1.5 0 1-5 60-90 5-15 0.5-1.5 0 1-2 74-90 5-15 0.5-1.5 00.1 73-94 5-15 0.5-1.5 0 0.5 76-92 5-15 0.5-1.5 0 1.0 74-90 5-15 0.5-1.50 2.0 69-85 5-15 0.5-1.5 0 5.0 55-71 5-15 0.5-1.5 0 8.0 41-57 5-150.5-1.5 0 10.0  32-48 5-15 0.5-1.5 0 0.1-10   4-89 5-15 0.5-1.5  1-580.1-2  57-88 5-15 0.5-1.5  1-23 1-5  8-57 5-15 0.5-1.5 12-58 1-2 57-735-15 0.5-1.5 12-23 0.1  76-93.5 5-15 0.5-1.5 0.5-2  0.5  66-89.5 5-150.5-1.5 2.5-10  1.0 54-85 5-15 0.5-1.5  5-20 2.0 29-75 5-15 0.5-1.510-40 5.0  1-46 5-15 0.5-1.5 25-59 8.0 0.3-32  5-15 0.5-1.5 25-56 10.0 0.1-12  5-15 0.5-1.5 25-47 0.1-10  38-94 10 0.5-1.5 0 0.1-2  75-94 100.5-1.5 0 1-5 60-90 10 0.5-1.5 0 1-2 74-90 10 0.5-1.5 0 0.1 73-94 100.5-1.5 0 0.5 76-92 10 0.5-1.5 0 1.0 74-90 10 0.5-1.5 0 2.0 69-85 100.5-1.5 0 5.0 55-71 10 0.5-1.5 0 8.0 41-57 10 0.5-1.5 0 10.0  32-48 100.5-1.5 0 0.1-10   4-89 10 0.5-1.5  1-58 0.1-2  57-88 10 0.5-1.5  1-231-5  8-57 10 0.5-1.5 12-58 1-2 57-73 10 0.5-1.5 12-23 0.1  76-93.5 100.5-1.5 0.5-2  0.5  66-89.5 10 0.5-1.5 2.5-10  1.0 54-85 10 0.5-1.5 5-20 2.0 29-75 10 0.5-1.5 10-40 5.0  1-46 10 0.5-1.5 25-59 8.0 0.3-32 10 0.5-1.5 25-56 10.0  0.1-12  10 0.5-1.5 25-47 0.1-10  38-94 5-15 0.8 00.1-2  75-94 5-15 0.8 0 1-5 60-90 5-15 0.8 0 1-2 74-90 5-15 0.8. 0 0.173-94 5-15 0.8 0 0.5 76-92 5-15 0.8 0 1.0 74-90 5-15 0.8 0 2.0 69-855-15 0.8 0 5.0 55-71 5-15 0.8 0 8.0 41-57 5-15 0.8 0 10.0  32-48 5-150.8 0 0.1-10   4-89 5-15 0.8  1-58 0.1-2  57-88 5-15 0.8  1-23 1-5  8-575-15 0.8 12-58 1-2 57-73 5-15 0.8 12-23 0.1  76-93.5 5-15 0.8 0.5-2  0.5 66-89.5 5-15 0.8 2.5-10  1.0 54-85 5-15 0.8  5-20 2.0 29-75 5-15 0.810-40 5.0  1-46 5-15 0.8 25-59 8.0 0.3-32  5-15 0.8 25-56 10.0  0.1-12 5-15 0.8 25-47 0.1-10  38-94 10 0.8 0 0.1-2  75-94 10 0.8 0 1-5 60-90 100.8 0 1-2 74-90 10 0.8 0 0.1 73-94 10 0.8 0 0.5 76-92 10 0.8 0 1.0 74-9010 0.8 0 2.0 69-85 10 0.8 0 5.0 55-71 10 0.8 0 8.0 41-57 10 0.8 0 10.0 32-48 10 0.8 0 0.1-10   4-89 10 0.8  1-58 0.1-2  57-88 10 0.8  1-23 1-5 8-57 10 0.8 12-58 1-2 57-73 10 0.8 12-23 0.1  76-93.5 10 0.8 0.5-2  0.5 66-89.5 10 0.8 2.5-10  1.0 54-85 10 0.8  5-20 2.0 29-75 10 0.8 10-405.0  1-46 10 0.8 25-59 8.0 0.3-32  10 0.8 25-56 10.0  0.1-12  10 0.825-47 MCC = microcrystalline cellulose TCP = tribasic calcium phosphate

6. EXAMPLES 6.1 Example 1: Preparation of DHE Powder Formulations

6.1.1 Preparation of 0.1 mg DHE Powder Formulation

Powder formulations comprising 0.1 mg DHE were prepared as describedherein.

Materials.

Dihydroergotamine mesylate (99.7% purity; primary particle distribution:Dv10: 5.3 μm; Dv50: 17.7 μm; Dv90: 69.3 μm; “DvX” refers to the maximumparticle diameter below which X % of the sample exists; for example,“Dv10” refers to the maximum particle diameter below which 10% of thesample exists); microcrystalline cellulose, Ceolus® PH-F20JP (nominalparticle size: 20 μm, less than 1% retained when sieved through meshsize 400; Asahi Kasei Chemicals Corporation); Microcrystallinecellulose, Ceolus® PH-301 (nominal particle size: 50 μm, less than 1%retained when sieved through mesh size 60 and less than 30% retainedwhen sieved through mesh size 200; Asahi Kasei Chemicals Corporation);Tribasic calcium phosphate (Ca₅(OH)(PO₄)₃; Mallinckrodt Chemicals); HPMCcapsule, size 2, Quali-V (Qualicaps Co., Ltd).

Procedure.

Two hundred-fifty mg Ceolus® PH-301 and 1110 mg Ceolus®PH-F20JP werecombined in a glass vial and mixed with vigorous shaking forapproximately 10 minutes. Twenty mg tribasic calcium phosphate was thenadded and mixed with vigorous shaking for approximately 10 minutes. Tenmg dihydroergotamine mesylate was then added and mixed with vigorousshaking for approximately 10 minutes. An additional 1110 mg Ceolus®PH-F20JP was then added and mixed with vigorous shaking forapproximately 10 minutes. The resulting DHE powder formulation wasencapsulated into the HPMC capsules (25 mg/capsule±1 mg) and the lengthof each capsule was adjusted to 17.8±0.4 mm using a capsule sizer.

6.1.2 Preparation of 0.5 mg DHE Powder Formulation

Powder formulations comprising 0.5 mg DHE were prepared as describedherein.

Materials.

Dihydroergotamine mesylate (99.7% purity; primary particle distribution:Dv10: 5.3 μm; Dv50: 17.7 μm; Dv90: 69.3 μm); microcrystalline cellulose,Ceolus® PH-F20JP (nominal particle size: 20 μm, less than 1% retainedwhen sieved through mesh size 400; Asahi Kasei Chemicals Corporation);Microcrystalline cellulose, Ceolus® PH-301 (nominal particle size: 50μm, less than 1% retained when sieved through mesh size 60 and less than30% retained when sieved through mesh size 200; Asahi Kasei ChemicalsCorporation); Tribasic calcium phosphate (Ca₅(OH)(PO₄)₃; MallinckrodtChemicals); HPMC capsule, size 2, Quali-V (Qualicaps Co., Ltd).

Procedure.

Sixty mg Ceolus® PH-301 and 261.6 mg Ceolus® PH-F20JP were combined in aglass vial and mixed with vigorous shaking for approximately 10 minutes.4.8 mg tribasic calcium phosphate was then added and mixed with vigorousshaking for approximately 10 minutes. Twelve mg dihydroergotaminemesylate was then added and mixed with vigorous shaking forapproximately 10 minutes. An additional 261.6 mg Ceolus® PH-F20JP wasthen added and mixed with vigorous shaking for approximately 10 minutes.The resulting DHE powder formulation was encapsulated into the HPMCcapsules (25 mg/capsule±1 mg) and the length of each capsule wasadjusted to 17.8±0.4 mm using a capsule sizer. Similar procedures werealso utilized to yield capsules with 1.5 mg±0.5 mg of such a 0.5 mg DHEpowder formulation per capsule.

6.1.3 Preparation of 1.0 mg DHE Powder Formulation

Powder formulations comprising 1.0 mg DHE were prepared as describedherein.

Materials.

Dihydroergotamine mesylate (99.7% purity; primary particle distribution:Dv10: 5.3 μm; Dv50: 17.7 μm; Dv90: 69.3 μm); microcrystalline cellulose,Ceolus® PH-F20JP (nominal particle size: 20 μm, less than 1% retainedwhen sieved through mesh size 400; Asahi Kasei Chemicals Corporation);Microcrystalline cellulose, Ceolus® PH-301 (nominal particle size: 50μm, less than 1% retained when sieved through mesh size 60 and less than30% retained when sieved through mesh size 200; Asahi Kasei ChemicalsCorporation); Tribasic calcium phosphate (Ca₅(OH)(PO₄)₃; MallinckrodtChemicals); HPMC capsule, size 2, Quali-V (Qualicaps Co., Ltd).

Procedure.

Sixty mg Ceolus® PH-301 and 255.6 mg Ceolus® PH-F20JP were combined in aglass vial and mixed with vigorous shaking for approximately 10 minutes.4.8 mg tribasic calcium phosphate was then added and mixed with vigorousshaking for approximately 10 minutes. Twenty-four mg dihydroergotaminemesylate was then added and mixed with vigorous shaking forapproximately 10 minutes. An additional 255.6 mg Ceolus®PH-F20JP wasthen added and mixed with vigorous shaking for approximately 10 minutes.The resulting DHE powder formulation was encapsulated into the HPMCcapsules (25 mg/capsule±1 mg) and the length of each capsule wasadjusted to 17.8±0.4 mm using a capsule sizer.

6.1.4 DHE Powder Formulations

Presented below, in Table 2, are representative DHE powder formulationsthat can be utilized in the methods of treating headache, includingmigraine, presented herein. Such formulations can be produced, forexample, following procedures as described in the preceding examples.The total amount of such formulations can be administered intranasallyinto a single nostril, or, alternatively, a portion can be administeredinto each nostril; for example, about one-half of the total can beadministered into each nostril.

TABLE 2 Components 0.1 mg 0.5 mg 1.0 mg 2.0 mg 5.0 mg DHE DHE DHE DHEDHE dose dose dose dose dose mg DHE 0.116 0.58 1.16 2.32 5.80 mesylateMCC (Ceolus 22.184 21.72 21.14 19.98 16.50 PH-F20JP) MCC (Ceolus 2.502.50 2.50 2.50 2.50 PH-301 Tribasic 0.20 0.20 0.20 0.20 0.20 calciumphosphate Total unit 25 25 25 25 25 dose wt Units: mgDHE—dihydroergotamine mesylate MCC (Ceolus PH-F20JP)—Microcrystallinecellulose nominal particle size 20 μm; less than 1% retained when sievedthrough mesh size 400. MCC (Ceolus PH 301)—Microcrystalline cellulosenominal particle size 50 μm; less than 1% retained when sieved throughmesh size 60 and less than 30% retained when sieved through mesh size200.

6.1.5 DHE Powder Formulations Comprising Caffeine

Presented below, in Table 3, are representative DHE powder formulationscomprising caffeine that can be utilized in the methods of treatingheadache, including migraine, presented herein. Such caffeine-containingformulations can be produced, for example, following procedures similarto those described in the preceding examples. The total amount of suchformulations can be administered intranasally into a single nostril, or,alternatively, a portion can be administered into each nostril; forexample, about one-half of the total can be administered into eachnostril.

TABLE 3 0.1 mg 0.5 mg 0.5 mg 1.0 mg 1.0 mg 2.0 mg 5.0 mg DHE DHE DHE DHEDHE DHE DHE Components dose dose dose dose dose dose dose DHE 0.116 0.580.58 1.16 1.16 2.32 5.80 mesylate Caffeine 0.29 1.45 1.25 2.9 2.5 5.814.5 anhydrous MCC (Ceolus 21.894 20.27 20.47 18.24 18.64 14.18 2.00PH-F20JP) MCC (Ceolus 2.50 2.50 2.50 2.50 2.50 2.50 2.50 PH-301 Tribasic0.20 0.20 0.20 0.20 0.20 0.20 0.20 calcium phosphate Total unit 25 25 2525 25 25 25 dose wt Units: mgs DHE—dihydroergotamine mesylate MCC(Ceolus PH-F20JP) - Microcrystalline cellulose nominal particle size 20um; less than 1% retained when sieved through mesh size 400. MCC (CeolusPH 301) - Microcrystalline cellulose nominal particle size 50 um; lessthan 1% retained when sieved through mesh size 60 and less than 30%retained when sieved through mesh size 200

6.2 Example 2: Pharmacokinetic Study of Intranasal DihydroergotamineFormulations in Primates

The study described herein is designed to assess the pharmacokinetics ofplasma dihydroergotamine (DHE) and 8′-hydroxy DHE levels afterintranasal administration using DHE powder formulations describedherein, and to compare the pharmacokinetic profiles achieved viaintranasal administration of such formulations with those of comparativeDHE formulations administered via various dosing routes.

The study utilizes Cynomolgus monkeys (Macaca fascicularis, purposebred) because the nasal cavity of such monkeys is morphologicallysimilar to that in humans, and is commonly used as an experimentalanimal.

Methods.

Animals.

Six male Cynomolgus monkeys (Macaca fascicularis, purpose bred), 4 to 6years old are used, following accredited animal welfare standards.

Test Powder Formulations.

Powder formulations containing 0.1 mg DHE, 0.5 mg DHE and 1.0 mg DHE, asdescribed in the Examples, above, and summarized in Table 3, above, aretested. With respect to the 0.5 mg DHE formulation, a 25 mg singlenostril dose is tested, as is a 12.5 mg two-nostril dose (total dose=25mg). Powder formulations containing 0.5 mg DHE containing 1.25 mganhydrous caffeine and 1.0 mg DHE containing 2.5 mg anhydrous caffeine,as summarized in Table xxx, above, are also tested. With respect to eachof the 0.5 mg DHE formulations, a 25 mg single nostril dose is tested,as is a 12.5 mg two-nostril dose (total dose=25 mg). The powderformulations are encapsulated as described in the Examples above, andare administered using a Fit-lizer™ intranasal dispenser (SNBL, LTD).

Comparative Formulations:

The following formulations and routes of administration are tested forcomparison purposes: IM DHE solution: 0.1 mg DHE mesylate of solution ofD.H.E. 45® (Valeant Pharmaceuticals North America) for intramuscular(IM) administration; IV DHE solution: 0.1 mL of D.H.E. 45® (ValeantPharmaceuticals North America) containing 0.1 mg DHE mesylate dilutedwith water for injection to 1.0 mL; 0.5 mg IN DHE solution: 0.5 mg DHEmesylate nasal spray (Migranal®; Valeant Pharmaceuticals North America);1.0 mg IN DHE solution: 1.0 mg DHE mesylate nasal spray (Migranal®;Valeant Pharmaceuticals North America); and 0.1 mg IN DHE solution: 0.1mg DHE mesylate (Migranal® diluted to 0.1 mg concentration with saline).

Dosing.

The dose levels of the DHE powder formulations are set at levelsequivalent to clinical doses of 0.1, 0.5, and 1.0 mg/body. Ascomparisons, the doses of the comparative formulations include ones setat the same levels as clinical doses of 1.0 mg/body for injection (IVand IM) and 0.5 mg/nostril for intranasal administration.

Powder DHE formulations are administered intranasally using a Fit-lizer®dispenser as noted above, and administration is confirmed by use of abreath monitoring device while holding the other nostril closed.

Intranasal solutions are administered using a device manually actuatedto deliver substance, and administration is confirmed by use of a breathmonitoring device while holding the other nostril closed.

Intramuscular injections are performed into the brachial muscle using adisposable needle and syringe.

Intravenous injections are administered into the cephalic vein of theforearm using a disposable needle and syringe. Volume/amountadministered per dose: 1.0 mL.

Sampling.

Blood sampling for pharmacokinetic analyses is performed each dosingday. The sampling points are as follows: Before dosing, 2, 5, 10, 15,20, 30, 45, 60, 120, 180, 240 and 480 minutes after dosing (total: 13points). In certain instances a 14^(th) point at 25 minutes after dosingis also performed. Blood is drawn from the femoral vein with a syringecontaining heparin sodium. The blood is immediately cooled on ice,centrifuged (4° C., 1710 cg, 3000 rpm, 15 minutes), and the plasma isstored in a deep freezer (−70° C. or below).

Pharmacokinetic Analysis.

An LC/MS/MS analytical method is utilized for determination of DHE and8′-hydroxy-DHE concentrations in plasma samples. C_(max), T_(max),AUC_(0-t) and T_(1/2) parameters are measured.

6.2.1 Results

Table 4 depicts the C_(max), T_(max), and AUC results from intranasaldosing of cynomolgous monkeys with 0.5 mg DHE mesylate nasal spray, thatis, Migranal (liquid formulation) and the DHE powder formulationsdescribed in Example 1. The corresponding PK curves of DHE in monkeyplasma after intranasal dosing with 0.5 mg of Migranal and 0.1, 0.5 and1.0 mg of the intranasal DHE powder are shown in FIGS. 1 and 2. The datain Table 4 and FIGS. 1 and 2 show that the intranasal powder formulationmaintains a short T_(max) (17.5-30 min) over all doses tested. In thisexample, the AUC_(0-t) (i.e., AUC_(0-480 minutes)) is tested 480 minutesafter administration of the powder formulation or Migranal.Additionally, the pharmacokinetic profile of IN powder DHE is improvedover the approved Migranal treatment. Specifically, the T_(max) valuesresulting from the IN powder are shorter than that resulting fromMigranal administration. Additionally, at the same DHE dose of 0.5 mg,the IN powder produces a 30% increase in DHE C_(max) over Migranal. Thisimproved PK is also reflected in FIG. 3, which shows that the DHE AUC inthe first 30 minutes post-dosing is higher in monkeys when dosed with INpowder vs. Migranal.

TABLE 4 PK parameters of DHE in cynomolgous monkeys after intranasaldosing C_(max) AUC_(0-t) AUC_(0-inf) T_(max) (ng/ml) (ng · h/mL) (ng ·h/mL) (min) IN Powder (0.1 mg) 1.82 5.01 5.72 17.5 IN Powder (0.5 mg)6.00 18.76 22.25 30.0 IN Powder (1.0 mg) 7.59 27.90 33.96 29.0 Migranal(0.5 mg) 4.65 16.20 19.15 45.0

FIG. 4 shows a comparison of DHE pharmacokinetic plasma concentrationcurves when dosed with DHE intranasal powder (0.5 mg DHE) with andwithout caffeine. The results shown in FIG. 4 not only demonstrate thatthe C_(max) was increased upon the addition of caffeine, but the T_(max)was also lowered. Moreover, the results in FIG. 5 demonstrate thatsplitting the dose of DHE intranasal powder between two nostrils resultsin an increased DHE C_(max) compared to administration of the full dosein one nostril. FIG. 6 presents plasma DHE concentrations in monkeysover 480 minutes after the tested administrations.

6.2.2 Conclusions

The results of this example demonstrate that intranasal administrationof powder formulations of dihydroergotamine described herein produce arapid onset and good exposure to DHE in primate plasma. When comparedwith the FDA approved Migranal intranasal DHE formulation, the IN DHEpowder formulations presented herein produce higher C_(max) values andshorter T_(max) values. Additionally, the exposure within the first 30minutes post-administration is improved with the IN DHE powderformulations. The improvement in these PK parameters is particularlyimportant in the treatment of migraine. Since DHE is generallyadministered to relieve an already occurring migraine, a faster onsetand greater exposure to the drug in a short period of time is an optimalpharmacokinetic profile. Lastly, the plasma exposure to the drug is evenfurther improved by adding caffeine to the IN DHE powder formulationand/or splitting the dose between two nostrils. These improvements in PKallow for administration of a lower dose of DHE to achievetherapeutically effective plasma levels.

6.3 Example 3: A Randomized, Open-Label, 5-Way Crossover Study toEvaluate the Pharmacokinetics, Dose Proportionality, Safety, andTolerability of Single Doses of Dihydroergotamine 1, 1.5, 2 and 3 μmgIntranasal Powder and Assess the Relative Bioavailability toDihydroergotamine 1 μmg Administered Subcutaneously as a Solution inHealthy Volunteers

The study described herein is designed to determine the pharmacokineticprofile, dose-proportionality, safety and tolerability of DHE intranasalpowder 1 mg, 1.5 mg, 2 mg and 3 mg in young healthy subjects and compareits bioavailability with DHE 1 mg administered subcutaneously as asolution. The pharmacokinetics of DHE and its metabolite(8′-β-hydroxydihydroergotamine; 8′-β-OH-DHE) are characterized in thisstudy.

Methodology.

This is a single-center, single-dose, randomized, open-label, 5-waycrossover, pharmacokinetic and safety study. Thirty (30) eligiblesubjects, not less than 40% or more than 60% of either gender, receivestudy medication in each of 5 treatment periods. Subjects are randomlyassigned to one of the 5 treatment sequences in accordance with apredetermined randomization schedule. The 5 treatment sequences are asfollows in Table 5:

TABLE 5 Period 1 Period 2 Period 3 Period 4 Period 5 Sequence TreatmentTreatment Treatment Treatment Treatment 1 A E B C D 2 B A C D E 3 C B DE A 4 D C E A B 4 E D A B C Treatment A = DHE 1 mg IN powder Treatment B= DHE 1.5 mg IN powder Treatment C = DHE 2 mg IN powder Treatment D =DHE 3 mg IN powder Treatment E = DHE 1 mg SC solution

During each treatment period, subjects are confined for 36 hoursapproximately. Subjects are admitted in the early evening before dosingof the each treatment period (approximately 12 hours before drugadministration) and remain in the clinical research unit untilapproximately 24 hours post-dose.

Study drug is administered in the morning, after an overnight fast of atleast 10 hours. Multiple blood samples for PK analysis are drawn over 24hours. A standardized lunch is provided within 4 to 5 hours afterdosing. A standardized dinner is provided at approximately 1800 hours.

There is a washout period of not less than 7 days between treatmentperiods. The duration of the washout period is measured from the lastday of the preceding period (approximately 24 hours post-dose) to dosingday of the subsequent period.

A safety follow-up visit takes place 7±2 days after the last treatmentperiod.

Patient Inclusion Criteria.

A subject is eligible for inclusion in this study only if all of thefollowing criteria apply:

-   -   Young healthy males or females, 18-45 years (inclusive) of age        at the time of enrollment, who have provided signed Informed        Consent and, if applicable, HIPAA authorization.    -   Healthy as judged by a responsible physician with no clinically        significant abnormality identified on the medical or laboratory        evaluation, including 12-lead ECG. A subject with a clinical        abnormality or laboratory parameters outside the reference range        for this age group may be included only if the Investigator        considers that the finding will not introduce additional risk        factors and will not interfere with the study procedures.    -   Subjects with a body mass index (BMI) ≥18 and ≤32 kg/m².    -   Female subjects are included if they are post-menopausal or        sterilized; or if they are of childbearing potential, they are        not breastfeeding, have a negative pregnancy test, have no        intention of becoming pregnant during the course of the study        and are using adequate contraceptive drugs or devices during the        course of this study. Medically acceptable methods of        contraception that may be used by the subject and/or her partner        are: oral contraceptives, progestin injection or implants,        condom with spermicide, diaphragm with spermicide, IUD, vaginal        spermicidal suppository combined with another barrier method of        contraception (condom, diaphragm), hormonal patch and vaginal        ring, surgical sterilization of their partner(s) or abstinence.        Females using oral contraception must have started using the        medication at least 4 weeks prior to screening. Surgical        sterilization of partners must have occurred at least 6 weeks        prior to screening.    -   Non-smokers (refrained from any tobacco usage, including        smokeless tobacco, nicotine patches, etc., for 6 months prior to        the administration of the study medication).    -   Subjects with intact nasal mucosa (no erythema, no inflammation,        no ulceration, no swelling, no bleeding, no atrophy (severe        local dryness and/or crusting), no septal perforation, and no        other nasal conditions that may interfere with IN dosing.    -   Subjects who are willing to abstain from alcohol for the 24        hours prior to first dose of study drug until the end of the        blood sampling period after the last treatment period.    -   Subjects who are willing and able to comply with the        requirements of the protocol and follow directions from the        clinic staff.    -   Subjects who are willing to avoid the consumption of grapefruit,        pomelo and Seville orange products and juices within 24 hours        prior to dosing of study drug until the end of the study.

Patient Exclusion Criteria.

A subject is excluded from this study if any of the following criteriaapply:

-   -   Any clinically significant central nervous system (e.g.,        seizures), cardiac, pulmonary, metabolic, renal, hepatic or        gastrointestinal conditions or history of such conditions that,        in the opinion of the investigator may place the subject at an        unacceptable risk as a participant in this trial or may        interfere with the absorption, distribution, metabolism or        excretion of drugs.    -   Abnormal physical findings of clinical significance at the        screening examination or baseline which would interfere with the        objectives of the study.    -   History of serious adverse reactions or hypersensitivity to any        drug, or who are known to be allergic to any of the test        product(s) or any components in the test product(s) or history        of hypersensitivity or allergic reactions to any of the study        preparations as described in the Investigator's Brochure.    -   Clinically significant abnormal laboratory values (as determined        by the Principal Investigator) at the screening evaluation.    -   12 lead ECG obtained at screening with: PR >240 msec, QRS>110        msec and QTc 430 msec, bradycardia (<50 bpm) or clinically        significant minor ST wave changes on the screening ECG, or any        other changes on the screening ECG that would interfere with        measurement of the QT interval.    -   History of orthostatic hypotension or orthostatic hypertension        present at screening.    -   Presence of an acute medical condition (e.g., diarrhea, fever,        upper respiratory viral infection) within 14 days of first        dosing in this study that is judged by the investigator to be        clinically significant.    -   Presence or history of allergies requiring acute or chronic        treatment (except seasonal allergic rhinitis).    -   Symptoms of a significant somatic or mental illness in the four        week period preceding drug administration    -   History or presence of migraine attacks in the last year.    -   Surgical interventions within 6 months of the study.    -   Has a positive pre-study Hepatitis B surface antigen; positive        hepatitis C (HCV) antibody or detectable HCV ribonucleic acid        (RNA); or positive HIV antibody result.    -   History of sensitivity to 5-HT_(1B/D) receptor agonists or to        heparin (if the clinical research unit uses heparin to maintain        intravenous cannula patency).    -   Use of any prescription (e.g., ergotamine containing or ergot        type medications (e.g., dihydroergotamine), or another        5-HT_(1B/D) receptor agonists), or nonprescription medications,        including vitamins and natural, herbal and dietary supplements        within 7 days or 5 half-lives (whichever is longer) prior to the        first dose of study medication, or use of St. John's Wort within        28 days prior to the first dose of study medication. However,        the Investigator and study team can review medication use on a        case by case basis to determine if its use would compromise        subject safety or interfere with study procedures or data        interpretation. By exception, the volunteer may take paracetamol        or acetaminophen (≤2 g/day) or ibuprofen (1600 mg/day) up to 48        hours prior to the first dose of study medication.    -   Subjects who use or have used other systemic prescription        medications, or any drugs (or herbal preparations) known to        inhibit CYP1A2 (for example fluvoxamine), CYP2D6 (for example        paroxetine, quinidine and fluoxetine), or CYP3A (for example        clarithromycin, itraconazole, ketoconazole, indinavir and        erythromycin) or induce CYP1A2 (for example rifampin) or CYP3A        (for example rifampin and carbamazepine) within 28 days prior to        dosing.    -   History of drug abuse or dependence within 12 months of the        study.    -   Has a history of regular alcohol consumption averaging >14        drinks/week (1 drink (12 g alcohol)=5 ounces (150 ml) of wine or        12 ounces (360 ml) of beer or 1.5 ounces (45 ml) of 80 proof        distilled spirits) within 6 months of the screening visit.    -   Loss of 500 ml blood or more during the 3 month period before        the study, e.g. blood donor.    -   The subject has a positive pre-study alcohol or urine drug        screen. A minimum list of drugs that will be screened for        include Amphetamines, Barbiturates, Cocaine, Opiates,        Cannabinoids and Benzodiazepines. (Suspected false positive        results may be repeated at the discretion of the Principal        Investigator.)    -   Concurrent participation in another drug research study or        within 60 days of enrollment.    -   Considered by the Investigator to be unsuitable candidate for        this study.

Outcome Measures.

Pharmacokinetics.

Pharmacokinetic sample collection: a total of 20 blood samples (6 mLeach) are collected at the following times: 0 (pre-dose), 5, 10, 15, 20,25, 30, 35, 40, and 45 minutes, and 1, 1.5, 2, 3, 4, 6, 8, 12, 18 and 24hours post-dose.

Safety/Tolerability.

The following assessment and measurements are conducted prior to dosingand/or at periodic intervals following dosing for up to 24 hours.

-   -   1. Physical examination    -   2. Vitals signs and body weight    -   3. 12-lead ECG    -   4. Blood tests for hematology and biochemistry analysis    -   5. Urinalysis    -   6. Adverse events (AEs)    -   7. Review of non-study medications received    -   8. Subjective assessment of nasal irritation: a questionnaire,        answered by the subject, concerning the presence of various        symptoms related to the nose    -   9. Brief Smell Identification Test (B-SIT™), a standardized test        of olfactory function.    -   10. Objective assessment of nasal irritation: a structures        examination of the nasal cavity and mucosal integrity.    -   11. Endoscopic examination of the nose if any clinical        significant abnormalities were observed in any of the above 3        assessments.    -   12. Suicidal evaluation with the Columbia Suicide-Severity        Rating Scale (C-SSRS).

Main Statistical Methods.

Pharmacokinetics.

The following pharmacokinetic parameters are calculated for both DHE andits major metabolite, 8′-β-hydroxydihydroergotamine, using standardnoncompartmental analysis:

-   -   1. Area under the concentration-time curves (AUC_(0-∞), and        AUC_(0-t))    -   2. Maximum observed plasma concentration (C_(max))    -   3. Time to reach C_(max) (T_(max))    -   4. Terminal half-life (t_(1/2))    -   5. Terminal rate constant (kel)    -   6. Ratio of AUC_(0-t) to AUC_(0-∞), (AUC_(0-t/0-∞))

Statistical analyses are performed using SAS®. All PK parameters arecalculated using the actual post-dose blood sampling times. Each timepoint is evaluated separately relative to the baseline value.Descriptive statistics [N, mean, standard deviation (SD), minimum,median, maximum and coefficient of variation (CV)] are used to summarizethe PK parameters for each treatment.

The study endpoints are:

-   -   1. Pharmacokinetics and dose proportionality of DHE 1 mg, 1.5        mg, 2 mg and 3 mg intranasal powder. Dose proportionality will        be determined by comparing AUC_(0-∞), AUC_(0-t) and C_(max) as        estimated from plasma DHE and 8′-β-OH-DHE concentration profiles        (Treatments A to D).    -   2. Pharmacokinetics of DHE 1 mg solution administered        subcutaneously (Treatment E).    -   3. Relative bioavailability of the DHE 1 mg intranasal powder        will be determined by comparing the AUC_(0-t), AUC_(0-∞) and        C_(max) of the intranasal powder (Treatment A) to those of the        DHE 1 mg subcutaneous solution (Treatment E).    -   4. Safety and tolerability of DHE in healthy adults following        intranasal powder administration (Treatments A to D).    -   5. Examination and reporting of all safety measures (i.e.        adverse events, vital signs and lab parameters) for all        treatments in the study.

The relative bioavailability of the DHE intranasal powder vs.subcutaneous solution is determined by examining the 90% confidenceinterval for the ratios of the test group (Treatment A) meanln-transformed AUC_(0-t), AUC_(0-∞) and C_(max), relative to thereference group means (Treatment E).

Dose proportionality within Treatments A and D, is assessed by fittingthe estimates of the ln-transformed parameters AUC_(0-∞), AUC_(0-t) andC_(max) for both dose levels to the power model. Individual slopes arederived for each subject. The power model is fitted with log (dose) atfixed effect and subjects as a random effect. The estimated mean slopeand 90% confidence intervals are constructed for each parameter. Theprimary criterion for dose proportionality for AUC_(0-∞), AUC_(0-t) andC_(max) is the inclusion of 1 within the range of the CIs, indicatingthe slope did not deviate significantly from 1.

Safety:

Safety analyses are conducted for the safety population which is definedas any volunteer who received study medication.

Safety labs including CBC, chemistry and urinalysis findings arecollected at baseline and end of each treatment period. Results fromlaboratory analyses are tabulated using descriptive statistics. Atabulation of by-volunteer abnormal/out-of-range findings is providedand changes from baseline to End of Period in all laboratory variablesare tabulated.

A standard 12-lead ECG is obtained at screening, at the beginning and atthe end of each treatment period and in the safety follow-up visit atthe end of the study. A tabulation of by-volunteer abnormal/out-of-rangefindings is provided and changes from baseline to End of Study variablesare tabulated.

6.4 Example 4: A Randomized, Open-Label, 5-Way Crossover Study toEvaluate the Pharmacokinetics, Bioavailability, Safety, and Tolerabilityof Single Doses of Dihydroergotamine 0.5 μMg and 1 μMg Intranasal Powderand Dihydroergotamine 0.5 μMg Administered Intravenously,Intramuscularly and Intranasally as a Solution in Healthy Volunteers

The study described herein is designed to determine the pharmacokineticprofile of DHE and its 8′-hydroxy-DHE metabolite, safety andtolerability of DHE intranasal powder 0.5 mg and 1 mg in young healthysubjects and compare its bioavailability with DHE 0.5 mg administeredintravenously, intramuscularly or as an intranasal solution.

Methodology.

This is a single-center, single-dose, randomized, open-label, 5-waycrossover, pharmacokinetic and safety study. Thirty (30) eligiblesubjects, not less than 40% or more than 60% of either gender, receivestudy medication in each of 5 treatment periods. Subjects are randomlyassigned to one of the 5 treatment sequences in accordance with apredetermined randomization schedule. The 5 treatment sequences are asfollows in Table 6:

TABLE 6 Period 1 Period 2 Period 3 Period 4 Period 5 Sequence TreatmentTreatment Treatment Treatment Treatment 1 A E B C D 2 B A C D E 3 C B DE A 4 D C E A B 4 E D A B C Treatment A = DHE 0.5 mg IN powder TreatmentB = DHE 1 mg IN powder Treatment C = DHE 0.5 mg IN solution Treatment D= DHE 0.5 mg IM solution Treatment E = DHE 0.5 mg IV solution

During each treatment period, subjects are confined for 36 hoursapproximately. Subjects are admitted in the early evening before dosingof the each treatment period (approximately 12 hours before drugadministration) and remain in the clinical research unit untilapproximately 24 hours post-dose.

Study drug is administered in the morning, after an overnight fast of atleast 10 hours. Multiple blood samples for PK analysis are drawn over 24hours. A standardized lunch is provided within 4 to 5 hours afterdosing. A standardized dinner is provided at approximately 1800 hours.

There is a washout period of not less than 7 days between treatmentperiods. The duration of the washout period is measured from the lastday of the preceding period (approximately 24 hours post-dose) to dosingday of the subsequent period.

A safety follow-up visit takes place 7±2 days after the last treatmentperiod.

Patient Inclusion Criteria.

A subject is eligible for inclusion in this study only if all of thefollowing criteria apply:

-   -   Young healthy males or females, 18-45 years (inclusive) of age        at the time of enrollment, who have provided signed Informed        Consent and, if applicable, HIPAA authorization.    -   Healthy as judged by a responsible physician with no clinically        significant abnormality identified on the medical or laboratory        evaluation, including 12-lead ECG. A subject with a clinical        abnormality or laboratory parameters outside the reference range        for this age group may be included only if the Investigator        considers that the finding will not introduce additional risk        factors and will not interfere with the study procedures.    -   Subjects with a body mass index (BMI) ≥18 and ≤32 kg/m².    -   Female subjects are included if they are post-menopausal or        sterilized; or if they are of childbearing potential, they are        not breastfeeding, have a negative pregnancy test, have no        intention of becoming pregnant during the course of the study        and are using adequate contraceptive drugs or devices during the        course of this study. Medically acceptable methods of        contraception that may be used by the subject and/or her partner        are: oral contraceptives, progestin injection or implants,        condom with spermicide, diaphragm with spermicide, IUD, vaginal        spermicidal suppository combined with another barrier method of        contraception (condom, diaphragm), hormonal patch and vaginal        ring, surgical sterilization of their partner(s) or abstinence.        Females using oral contraception must have started using the        medication at least 4 weeks prior to screening. Surgical        sterilization of partners must have occurred at least 6 weeks        prior to screening.    -   Non-smokers (refrained from any tobacco usage, including        smokeless tobacco, nicotine patches, etc., for 6 months prior to        the administration of the study medication).    -   Subjects with intact nasal mucosa (no erythema, no inflammation,        no ulceration, no swelling, no bleeding, no atrophy (severe        local dryness and/or crusting), no septal perforation, and no        other nasal conditions that may interfere with IN dosing.    -   Subjects who are willing to abstain from alcohol for the 24        hours prior to first dose of study drug until the end of the        blood sampling period after the last treatment period.    -   Subjects who are willing and able to comply with the        requirements of the protocol and follow directions from the        clinic staff.    -   Subjects who are willing to avoid the consumption of grapefruit,        pomelo and Seville orange products and juices within 24 hours        prior to dosing of study drug until the end of the study.

Patient Exclusion Criteria.

A subject is ineligible for inclusion in this study if any of thefollowing criteria apply:

-   -   Any clinically significant central nervous system (e.g.,        seizures), cardiac, pulmonary, metabolic, renal, hepatic or        gastrointestinal conditions or history of such conditions that,        in the opinion of the investigator may place the subject at an        unacceptable risk as a participant in this trial or may        interfere with the absorption, distribution, metabolism or        excretion of drugs.    -   Abnormal physical findings of clinical significance at the        screening examination or baseline which would interfere with the        objectives of the study.    -   History of serious adverse reactions or hypersensitivity to any        drug, or who are known to be allergic to any of the test        product(s) or any components in the test product(s) or history        of hypersensitivity or allergic reactions to any of the study        preparations as described in the Investigator's Brochure.    -   Clinically significant abnormal laboratory values (as determined        by the Principal Investigator) at the screening evaluation.    -   12 lead ECG obtained at screening with: PR >240 msec, QRS>110        msec and QTc 430 msec, bradycardia (<50 bpm) or clinically        significant minor ST wave changes on the screening ECG, or any        other changes on the screening ECG that would interfere with        measurement of the QT interval.    -   History of orthostatic hypotension or orthostatic hypertension        present at screening.    -   Presence of an acute medical condition (e.g., diarrhea, fever,        upper respiratory viral infection) within 14 days of first        dosing in this study that is judged by the investigator to be        clinically significant.    -   Presence or history of allergies requiring acute or chronic        treatment (except seasonal allergic rhinitis).    -   Symptoms of a significant somatic or mental illness in the four        week period preceding drug administration    -   History or presence of migraine attacks in the last year.    -   Surgical interventions within 6 months of the study.    -   Has a positive pre-study Hepatitis B surface antigen; positive        hepatitis C (HCV) antibody or detectable HCV ribonucleic acid        (RNA); or positive HIV antibody result.    -   History of sensitivity to 5-HT_(1B/D) receptor agonists or to        heparin (if the clinical research unit uses heparin to maintain        intravenous cannula patency).    -   Use of any prescription (e.g., ergotamine containing or ergot        type medications (e.g., dihydroergotamine), or another        5-HT_(1B/D) receptor agonists), or nonprescription medications,        including vitamins and natural, herbal and dietary supplements        within 7 days or 5 half-lives (whichever is longer) prior to the        first dose of study medication, or use of St. John's Wort within        28 days prior to the first dose of study medication. However,        the Investigator and study team can review medication use on a        case by case basis to determine if its use would compromise        subject safety or interfere with study procedures or data        interpretation. By exception, the volunteer may take paracetamol        or acetaminophen (≤2 g/day) or ibuprofen (1600 mg/day) up to 48        hours prior to the first dose of study medication.    -   Subjects who use or have used other systemic prescription        medications, or any drugs (or herbal preparations) known to        inhibit CYP1A2 (for example fluvoxamine), CYP2D6 (for example        paroxetine, quinidine and fluoxetine), or CYP3A (for example        clarithromycin, itraconazole, ketoconazole, indinavir and        erythromycin) or induce CYP1A2 (for example rifampin) or CYP3A        (for example rifampin and carbamazepine) within 28 days prior to        dosing.    -   History of drug abuse or dependence within 12 months of the        study.    -   Has a history of regular alcohol consumption averaging >14        drinks/week (1 drink (12 g alcohol)=5 ounces (150 ml) of wine or        12 ounces (360 ml) of beer or 1.5 ounces (45 ml) of 80 proof        distilled spirits) within 6 months of the screening visit.    -   Loss of 500 ml blood or more during the 3 month period before        the study, e.g. blood donor.    -   The subject has a positive pre-study alcohol or urine drug        screen. A minimum list of drugs that will be screened for        include Amphetamines, Barbiturates, Cocaine, Opiates,        Cannabinoids and Benzodiazepines. (Suspected false positive        results may be repeated at the discretion of the Principal        Investigator.)    -   Concurrent participation in another drug research study or        within 60 days of enrollment.    -   Considered by the Investigator to be unsuitable candidate for        this study.

Outcome Measures.

Pharmacokinetics:

Pharmacokinetic sample collection: a total of 20 blood samples (6 mLeach) are collected at the following times: 0 (pre-dose and immediatelypost-dose in the IV arm), 5, 10, 15, 20, 25, 30, 35, 40, and 45 minutes,and 1, 1.5, 2, 3, 4, 6, 8, 12, 18 and 24 hours post-dose.

Safety/Tolerability:

The following assessment and measurements will be conducted prior todosing and/or at periodic intervals following dosing for up to 24 hours.

-   -   Physical examination    -   Vitals signs and body weight    -   12-lead ECG    -   Blood tests for hematology and biochemistry analysis    -   Urinalysis    -   Adverse events (AEs)    -   Review of non-study medications received    -   Subjective assessment of nasal irritation: a questionnaire,        answered by the subject, concerning the presence of various        symptoms related to the nose    -   Brief Smell Identification Test (B-SIT™), a standardized test of        olfactory function.    -   Objective assessment of nasal irritation: a structures        examination of the nasal cavity and mucosal integrity.    -   Endoscopic examination of the nose if any clinical significant        abnormalities were observed in any of the above 3 assessments.    -   Suicidal evaluation with the Columbia Suicide-Severity Rating        Scale (C-SSRS).

Main Statistical methods (including required subject numberrequirement):

Pharmacokinetics.

The following pharmacokinetic parameters are calculated for both DHE andits major metabolite, 8′-β-hydroxydihydroergotamine, using standardnoncompartmental analysis:

-   -   1. Area under the concentration-time curves (AUC_(0-∞), and        AUC_(0-t))    -   2. Maximum observed plasma concentration (C_(max))    -   3. Time to reach C_(max) (T_(max))    -   4. Terminal half-life (t_(1/2))    -   5. Terminal rate constant (kel)    -   6. Ratio of AUC_(0-t) to AUC_(0-∞) (AUC_(0-t/0-∞))

Statistical analyses are performed using SAS®. Plasma concentrations andpharmacokinetic parameters are summarized descriptively by treatmentgroup and time point, where appropriate. All PK parameters arecalculated using the actual post-dose blood sampling times. Each timepoint is evaluated separately relative to the baseline value.Descriptive statistics [N, mean, standard deviation (SD), minimum,median, maximum and coefficient of variation (CV)] are used to summarizethe PK parameters for each treatment.

The study endpoints are:

-   -   1. Pharmacokinetics and dose proportionality of DHE 0.5 and 1 mg        intranasal powder. Dose proportionality is determined by        comparing AUC_(0-∞), AUC_(0-t) and C_(max) as estimated from        plasma DHE and 8′-β-OH-DHE concentration profiles (Treatments A        and B).    -   2. Pharmacokinetics of DHE 0.5 mg solution administered        intravenously, intramuscularly and intranasally (Treatments C, D        and E).    -   3. Absolute and relative bioavailability of the DHE 0.5 mg        intranasal powder are determined by comparing the AUC_(0-t),        AUC_(0-∞) and C_(max) of the intranasal powder (Treatment A) to        those of the DHE 0.5 mg intravenous, intramuscular and        intranasal solutions (Treatments C, D and E).    -   4. Safety and tolerability of DHE in healthy adults following        intranasal powder administration (Treatments A and B).    -   5. Examination and reporting of all safety measures (i.e.        adverse events, vital signs and lab parameters) for all        treatments in the study.

The absolute and relative bioavailability of the DHE intranasal powdervs. intravenous and intramuscular and intranasal solution are determinedby examining the 90% confidence interval for the ratios of the testgroup (Treatment A) mean ln-transformed AUC_(0-t), AUC_(0-∞) andC_(max), relative to the reference group means (Treatments C, D, and E).

Dose proportionality within Treatments A and B, are assessed by fittingthe estimates of the ln-transformed parameters AUC_(0-∞), AUC_(0-t) andC_(max) for both dose levels to the power model. Individual slopes willbe derived for each subject. The power model is fitted with log (dose)at fixed effect and subjects as a random effect. The estimated meanslope and 90% confidence intervals are constructed for each parameter.The primary criterion for dose proportionality for AUC_(0-∞), AUC_(0-t)and C_(max) is the inclusion of 1 within the range of the CIs,indicating the slope did not deviate significantly from 1.

Safety.

Safety analyses are conducted for the safety population which is definedas any volunteer who received study medication.

All adverse events reported during the study are listed, documentingcourse, severity, possible relationship to study medication and outcome.Verbatim terms on the case report forms are classified to preferredterms and related system organ class using the MedDRA dictionary. Thepreferred terms and system organ classes are tabulated by treatmentgroup and study period. All reported adverse events are summarized bythe number of volunteers reporting adverse events, system organ class,preferred term, severity and relationship to study drug. All adverseevents are presented in data listings indexed by volunteer.

Safety labs including CBC, chemistry and urinalysis findings arecollected at baseline and end of each treatment period. Results fromlaboratory analyses are tabulated using descriptive statistics. Atabulation of by-volunteer abnormal/out-of-range findings is providedand changes from baseline to End of Period in all laboratory variablesare tabulated.

A standard 12-lead ECG is obtained at screening, at the beginning and atthe end of each treatment period and in the safety follow-up visit atthe end of the study. A tabulation of by-volunteer abnormal/out-of-rangefindings is provided and changes from baseline to End of Study variablesare tabulated.

6.5 Example 5: Treatment of Migraine with Dihydroergotamine IntranasalPowder Formulation

The DHE nasal powder formulation is indicated for rapid onset treatmentof acute migraine with or without aura. Patients are instructed to usethe product when they have an active migraine headache. Specifically,prior to use, patients are instructed to blow their nose gently to helpopen the nasal passages. If the entire dose is to be delivered in asingle nostril, the patient is instructed to select the nostril with thebetter airflow. Some physicians may consider using the DHE nasal powderin their office or in a medical setting. The total amount of DHE in asingle dose ranges from about 0.1 to 10 mg. Typically, a patientreceives a dose of about 1.0 to 2.0 mg. DHE nasal powder with or withoutcaffeine may be administered to the patient.

DHE Nasal Powder Presentation.

The DHE nasal powder formulation is delivered using a dispenser. Thedispenser primarily consists of a squeeze bottle with a nozzleapproximately half an inch long. The squeeze bottle functions as a pumpand the nozzle, which normally holds the powder at its base, alsotargets and guides the delivery of the powder into the nostril. Thesqueeze bottle can be configured as a disposable single-unit dosedelivery system or a multiple dose delivery. It can also be configuredto be refilled with the powder once the pre-filled dispenser is fullyused. The dispenser containing the formulation can also be configured todeliver each dose in a single or a double puff without priming. Thepowder from the dispenser can be administered in either nostril or bothnostrils.

Exclusions.

Patients are instructed not to use the product to prevent a headache ifthey have no prodromal symptoms of migraine such as changes in mentalstate including irritability or confusion, and physical signs includingthirst or diarrhea. Any migraine patient who is pregnant or nursing, hasany cardiovascular diseases, or taking anti-HIV medications, or takingmacrolide antibiotic such as troleandomycin, clarithromycin orerythromycin is instructed not to use the DHE nasal powder formulation.Similarly, migraine patients taking triptans are instructed not to usethe DHE nasal powder and conversely, patients using the DHE nasal powderare instructed not to simultaneously use triptans for the treatment ofmigraine.

INCORPORATION BY REFERENCE

Various references such as patents, patent applications, andpublications are cited herein, the disclosures of which are herebyincorporated by reference herein in their entireties. In the event of aconflict between a term herein and a term incorporated by reference, theterm herein controls.

What is claimed is:
 1. A pharmaceutical nasal dosage form, comprising: dihydroergotamine or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient for treating migraine with or without aura in a human subject, wherein said pharmaceutical nasal dosage form is provided in a pre-primed nasal device.
 2. The pharmaceutical nasal dosage form of claim 1, wherein said pharmaceutical nasal dosage form requires less than about 15 minutes to administer an effective dose of dihydroergotamine.
 3. The pharmaceutical nasal dosage form of claim 2, wherein said pharmaceutical nasal dosage form requires a single spray or two sprays to administer said effective dose of dihydroergotamine.
 4. The pharmaceutical nasal dosage form of claim 2, wherein said effective dose of dihydroergotamine is from about 0.5 mg to about 2 mg.
 5. The pharmaceutical nasal dosage form of claim 1, wherein said dihydroergotamine or said pharmaceutically acceptable salt thereof is present from about 0.5 mg to about 10 mg.
 6. The pharmaceutical nasal dosage form of claim 1, wherein said dihydroergotamine or said pharmaceutically acceptable salt thereof is present from about 1.5 mg to about 6 mg.
 7. The pharmaceutical nasal dosage form of claim 1, wherein said pharmaceutical nasal dosage form comprises said pharmaceutically acceptable salt of dihydroergotamine that is dihydroergotamine mesylate.
 8. The pharmaceutical nasal dosage form of claim 1, wherein said pharmaceutically acceptable excipient comprises microcrystalline cellulose.
 9. The pharmaceutical nasal dosage form of claim 8, wherein said microcrystalline cellulose is present in an amount of about 15% to 99% of a total weight of said pharmaceutical nasal dosage form.
 10. The pharmaceutical nasal dosage form of claim 8, wherein said microcrystalline cellulose component has a mean particle size diameter of about 100 μm or less.
 11. The pharmaceutical nasal dosage form of claim 8, wherein said microcrystalline cellulose component has a mean particle size diameter of about 30 μm or less.
 12. A method comprising administering a pharmaceutical nasal dosage form of dihydroergotamine or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient, wherein said pharmaceutical nasal dosage form is administered using a pre-primed nasal device and requires less than four sprays to administer an effective dose of dihydroergotamine for treating migraine with or without aura in a human subject.
 13. The method of claim 12, wherein said pharmaceutical nasal dosage form requires less than about 15 minutes for said administration.
 14. The method of claim 12, wherein said effective dose is from about 0.5 mg to about 2 mg of dihydroergotamine.
 15. The method of claim 12, wherein said effective dose is from about 1.5 mg to about 6 mg of dihydroergotamine.
 16. The method of claim 12, wherein said administration comprises two sprays.
 17. The method of claim 12, wherein said pharmaceutically acceptable excipient comprises microcrystalline cellulose.
 18. The method of claim 12, wherein said pharmaceutical nasal dosage form upon intranasal administration to a human subject provides at least about 10% higher AUC_(0-t), AUC_(0-inf), or AUC_(0-30 min), compared to a corresponding liquid form.
 19. The method of claim 12, wherein said pharmaceutical nasal dosage form upon intranasal administration to a human subject provides at least about 10% reduction in time required to achieve C_(max) or a plasma concentration of at least about 700 pg/ml, compared to a corresponding liquid form.
 20. The method of claim 12, wherein said pharmaceutical nasal dosage form upon intranasal administration to a human subject provides at least one of the following pharmacokinetic parameters: C_(max) of at least 900 pg/mL; AUC_(0-t) of at least 1000 pg*hr/mL; and AUC_(0-inf) of at least 5000 pg*hr/mL. 